Effects of Fermented Mealworm(Tenebrio molitor Larva) Extract on Metabolic Regulation and Intestinal Microflora in Rats with Chronic Alcohol-Induced Hepatic Steatosis

다국어 초록 (Multilingual Abstract)

This study investigated the protective effects of defatted mealworm (Tenebrio molitor larva) fermentation extract (FME) on alcoholic hepatosteatosis and its underlying mechanism, and elucidated the changes in the serum metabolic profiles and intestinal microflora in chronic alcohol-fed rats. The rats were fed a Lieber-Decarli liquid diet, containing either isocaloric maltose dextrin (Con) or 5% (w/v) alcohol (EtOH). The FME (50, 100, and 200 mg/kg) and silymarin (200 mg/kg) were administered orally once a day to the rats fed alcohol for eight weeks. The FME50 and FME200 groups showed an attenuation of the alcoholic liver damage, as illustrated by reduced serum damage markers (AST, ALT, and γ-GTP) and relative liver weight compared to the EtOH group. Hepatic histological observations showed that all doses of FME and silymarin inhibited lipid vacuolar deposition (Oil Red O), fat size (H&E), and degree of fibrosis (Trichrome). All doses of FME and silymarin lowered the hepatic phosphatidate phosphohydrolase activity significantly compared to those in the EtOH group, but increased the β-oxidation activity in a dose-dependent manner. The FME200 group effectively improved the alcohol-induced hepatic steatosis by down regulating the hepatic lipid synthesis-related transcriptional factors (ChREBP, SREBP-1c, and SREBP-2) and their downstream genes (GPAT1, GPAT4, AGPAT1, PAP1, DGAT1, ADRP, HMGCR, and ACAT2). The FME enhanced antioxidant activity by elevating the hepatic glutathione (GSH) contents and glutathione reductase activity. The FME100 and FME200 groups showed a significantly smaller response to alcoholic inflammation through the down-regulation of hepatic phosphorylated-inhibitor of nuclear factorkappa B-alpha and tumor necrosis factor-alpha (TNF-α) compared to the EtOH group.
All doses of FME and silymarin reversed the increased serum acetaldehyde and TNF-α concentrations, and hepatic hydrogen peroxide levels induced by alcohol. In the serum metabolomics study, 3-hydroxybutyric acid, pyroglutamic acid, octadecanoic acid, and docosahexaenoic acid were evaluated as high variable importance point scores and principal component analysis (PCA) loading scores by partial least squares discriminant
analysis and PCA. Their levels were significantly higher in the FME group than the EtOH group. These metabolites were involved in the β-oxidation activity, GSH synthesis, free fatty acid absorption into the liver, and regulation of inflammatory responses, respectively. Furthermore, sequencing analysis of the gut microbiota showed that the FME tended to increase the number of Lactobacillus johnsonii reduced by alcohol intake. In conclusion, the hepatoprotective effects of FME (200 mg/kg) were related to the lipid metabolism, inflammatory response, and GSH contents, and were more effective than silymarin (200 mg/kg). In addition, the metabolite pattern was similar to that of silymarin.

목차 (Table of Contents)

• I. Introduction . 1
• 1. Alcoholic liver disease (ALD) . 1
• 2. Alcohol and its related metabolism in liver 6
• 3. Gut microbiota and ALD 20
• 4. Edible insects in liver disease . 22
• 5. Pharmacological properties of mealworm (Tenebrio molitor larva) 26
• 6. The purpose of study 30
• Ⅱ. Materials and Methods . 31
• 1. Preparation of fermented mealworm extract (FME) 31
• 2. Experimental design and diet . 33
• 3. Serum biochemical analysis . 37
• 4. Serum lipid profiles 39
• 5. Hepatic and fecal lipid profiles 41
• 6. Hepatic histological analysis 41
• 7. Tissue preparation for samples . 42
• 8. Hepatic alcohol metabolic enzyme activities . 43
• 9. Hepatic lipid metabolic enzyme activities 44
• 10. Hepatic antioxidant enzyme activities 46
• 11. Hepatic glutathione and hydrogen peroxide levels 49
• 12. Hepatic gene expression . 50
• 13. Western blot analysis 55
• 14. Metabolomics analysis in serum 56
• 15. Microbial community analysis in colon . 59
• 16. Statistical analysis 60
• Ⅲ. Results . 61
• 1. Effects of FME on body weight, food intake, and organ weights 61
• 2. Effects of FME on serum parameters . 65
• 3. Effects of FME on hepatic steatosis . 68
• 4. Effects of FME on inflammatory response 89
• 5. Effects of FME on antioxidant defense system 93
• 6. Effects of FME on alcohol metabolism 97
• 7. Effects of FME on targeted serum metabolite profiling . 101
• 8. Effects of FME on bacterial community composition 114
• Ⅳ. Discussion . 123
• 1. FME ameliorated alcoholic hepatic steatosis . 123
• 2. FME attenuated alcohol-induced inflammation and enhanced antioxidant activity 127
• 3. A link of serum metabolites and hepatic metabolic pathway in FME 133
• 4. FME modulated the changes of gut microbial community caused by alcohol . 138
• Ⅴ. Conclusion 140
• References . 141
• Abstract in Korean . 176
• Acknowledgment 179

참고문헌 (Reference)

1. Alcohol metabolism, Cederbaum AI, Clin . Liver Dis . 16 : 667-685, , 2012

2. Bioactive peptides, Daliri EBOh DHLee BH, Foods 6 : 32, , 2017

3. Metabolism of alcohol, Lieber CS, Clin . Liver Dis . 9 : 1-35, , 2005

4. H. Alcoholic Liver Disease, Seitz , H.K .Bataller , R.Cortez-Pinto , H.Gao , B.Gual , A.Lackner , C.Mathurin , P.Mueller , S.Szabo , G.Tsukamoto, Nat . RevDis . Primers4 , 1 ? 22 . [ CrossRef, , 2018

5. Methods of enzymatic analysis, 173 . BergmeyerHU ., Alcohol dehydrogenase . New York : Academic Press Inc. p 428-429, , 1974

6. H. Methods in enzymatic analysis, 181 . Aebi, Bergmeyer , HU ed . Catalase . New York : Academic Press Inc. p 673-684, , 1974

7. Managing alcoholic liver disease, Shah VH, Clin . Mol . Hepatol21 : 212-219, , 2015

8. Deaths : preliminary data for 2004, o AMHeron MPSmith BL, Vital . Stat . Rep. 54 : 1-49, , 2006

9. Fatty acid synthase from rat liver, 176 . Nepokroeff CMLakshmanan MRPorter JW, Methods Enzymol . 35 : 37-44, , 1975

10. Gut bacteria in health and disease, Quigley EM, Gastroenterol . Hepatol9 : 560- 569, , 2013

11. P. Focus on : Alcohol and the Liver, Szabo , G.Mandrekar, Alcohol Res . Health33 , 87 ? 96, , 2010

12. Obesity alters gut microbial ecology, Ley REckhed FTurnbaugh PLozupone CAKnight RDGordon JI, Proc . Natl . Acad . SciU.S.A. 102 : 11070-11075, , 2005

13. Tsukamoto H. Alcoholic liver disease, Seitz HKBataller RCortez-Pinto HGao BGual ALackner CMathurin PMueller SSzabo G, Nat . RevDis . Primers . 4 : 1-22, , 2018

14. liver disease and the gut microbiota, Bajaj JS, Nat . Rev . Gastroenterol . Hepatol16 : 235-246, , Alcohol2019

15. Effect of ethanol on lipid metabolism, You MArteel GE, J. Hepatol70 , 237 ? 248 . [ CrossRef, , 2019

16. A mathematical theory of communication, Shannon CE, Bell . Syst . Tech . J . 27 : 379-423 . 1948,

17. D. Cytokines in alcoholic liver disease, McClain , CJBarve , SDeaciuc , IKugelmas , M , Hill, Semin . Liver Dis . 19 : 205-219, , 1999

18. Inflammation in alcoholic liver disease, Wang HJGao BZakhari SNagy LE, Annu . Rev . Nutr . 32 : 343-368, , 2012

19. R. Multivariate Analysis in Metabolomics, Worley , B.Powers, Curr . MetabolomicsPubMed, , 2013

20. Tilg H. Cytokines and fatty liver diseases, Niederreiter L, Liver Res . 2 : 14-20, , 2018

21. oxidative stress , and free radical damage, Wu DCederbaum AI, Alcohol ResHealth 27 : 277-284, , Alcohol2003

22. Molecular mechanism of alcoholic fatty liver, Rasineni KCasey CA, Indian J. Pharmacol . 44 : 299-303, , 2012

23. a human intestinal mucin-degrading bacterium, DerrienM. , VaughanE.E. , PluggeC.M .de VosW.M . Akkermansia muciniphila gen. nov.sp . nov., Int . J. Syst . Evol . Microbiol . 54 : 1469-1476, , 2004

24. Mandrekar P. Focus on : alcohol and the liver, Szabo G, Alcohol ResHealth 33 : 87-96, , 2010

25. . ; Lee , D.S . Pathogenesis , Early Diagnosis, , L.Z . ;, N. ;, Y.H . ;, D.H. ; KimJ.S . ; KimS.U . ; KimT.D . ; JeongD.K . ; Sun ,, and Therapeutic Management of Alcoholic Liver. J. Mol . Sci ., , .

26. Medici V. Diagnosis of alcoholic liver disease, Torruellas CFrench SW, World J. Gastroenterol20 : 11684-11699, , 2014

27. Role of mitochondria in alcoholic liver disease, a-Ruiz CKaplowitz NFernandez-Checa JC, Curr . Pathobiol . Rep. 1 : 159-168, , 2013

28. Assay of peroxisomal β-oxidation of fatty acids, Lazarow PB, Enzymol . 72 : 315-319, , 1981

29. Epidemiology of alcoholic liver disease in Korea, Jang JYKim DJ, Clin . Mol . Hepatol24 : 93-99, , 2018

30. Li F. Edible insects as a food source : a review, Tang CYang DLiao HSun HLiu CWei L, Food ProductionProcessing and Nutrition 1 : 8, , 2019

31. Diversity of the human intestinal microbial flora, Eckburg PBBik EMBernstein CNPurdom EDethlefsen LSargent MGill SRNelson KERelman DA, Science 308 : 1635-1638, , 2005

32. E. Current Opinion in Pediatric Metabolic Disease, Mayatepek, J. Pediat . Sci3 , e64, , 2011

33. Transcriptional regulation of hepatic lipogenesis, Wang YViscarra JKim SJSul HS, Nat . Rev . Mol . Cell Biol16 : 678-689, , 2015

34. Review of food composition data for edible insects, Nowak VPersijn DRittenschober DCharrondiere UR, Food Chem193 , 39 ? 46 . [ CrossRef, , 2016

35. Adipophilin , and TIP47 package lipid in adipocytes, Wolins NEQuaynor BKSkinner JRSchoenfish MJTzekov ABickel PE . S3-12, J. Biol . Chem280 : 19146- 19155, , 2005

36. Carr R. Alcohol effects on hepatic lipid metabolism, Jeon S, J. Lipid Res61 : 470- 479, , 2020

37. Kalayci O. Oxidative stress and antioxidant defense, Birben ESahiner UMSackesen CErzurum S, World Allergy Organ J . 5 : 9-19, , 2012

38. Knight R. Evolution of mammals and their gut microbes, Ley REHamady MLozupone CTurnbaugh PJRamey RRBircher JSSchlegel MLTucker TASchrenzel MD, Science 320 : 1647-1651, , 2008

39. Lu Y. Alcoholic liver disease : from CYP2E1 to CYP2A5, Ming Leung T, Curr . Mol . Pharmacol10 : 172-178, , 2017

40. Alcohol and mitochondria : a dysfunctional relationship, Hoek JBCahill APastorino JG, Gastroenterology 122 : 2049-2063, , 2002

41. M. Resveratrol Alleviates Alcoholic Fatty Liver in Mice, Ajmo , J.M .Liang , X.Rogers , C.Q .Pennock , B.You, Am . J. Physiol . Gastrointest . Liver Physiol295 , G833 ? G842 . [ CrossRef, , 2008

42. Feng W. Microbiome dysbiosis and alcoholic liver disease, Li FMcClain CJ, Liver Res . 3 : 218-226, , 2019

43. Cautiously using natural medicine to treat liver problems, Xiong FGuan YS, World J. Gastroenterol . 23 : 3388-3395, , 2017

44. Long-chain acyl-CoA synthetases and fatty acid channeling, Mashek DGLi LOColeman RA, Future Lipidol . 2 : 465-476, , 2007

45. Role of variability in explaining ethanol pharmacokinetics, Jones AWHahn RGGabrielsson JL, Clin . Pharmacokinet . 42 : 1-31, , 2003

46. systematic review and recent clinical trials of metadoxine, Di Miceli MGronier B. Pharmacology, Rev . Recent ClinTrials . 13 : 114-125, , 2018

47. D. Cytokines in Alcoholic Liver Disease . Semin . Liver Dis, McClain , C.J .Barve , S.Deaciuc , I.Kugelmas , M., 19 , 205 ? 219 . [ CrossRef, , 1999

48. Keshavarzian A. Colonic microbiome is altered in alcoholism, Mutlu EAGillevet PMRangwala HSikaroodi MNaqvi AEngen PAKwasny MLau CK, Am . J. Physiol . Gastrointest . Liver . Physiol . 302 : G966-G978, , 2012

49. Mayatepek E. Current opinion in pediatric metabolic disease, 230 ., J. Pediatr . Sci . 3 : e69, , 2011

50. You M. Resveratrol alleviates alcoholic fatty liver in mice, 245 . Ajmo JMLiang XRogers CQPennock B, Am . J. Physiol . Gastrointest . Liver Physiol . 295 : G833-G842, , 2008

51. Kaplowitz N. Importance and regulation of hepatic glutathione, Deleve LD, Semin . Liver Dis . 10 : 251-266, , 1990

52. Dongiovanni P. Alcohol or gut microbiota : who is the guilty ?, Meroni MLongo M, Int . J. Mol . Sci20 : 4568, , 2019

53. Fermented edible insects for promoting food security in Africa, Kewuyemi YOKesa HChinma CEAdebo OA, Insects 11 : 283, , 2020

54. 122. Jongema Y. 2017 List of edible insects of the world, 2019., Jongema Y, , 20172019

55. gut microbiota , and their influence on host health and disease, nchez BDelgado SBlanco ? Mguez Ao AGueimonde MMargolles A. Probiotics, Mol . Nutr . Food Res61 : 1600240, , 2017

56. Systematic Review and Recent Clinical Trials of Metadoxine . Rev, Di Miceli , M.Gronier , B. Pharmacology, Recent Clin . Trials13 , 114 ? 125 . [ CrossRef, , 2018

57. O. Oxidative Stress and Antioxidant Defense . World Allergy Organ, Birben , E.Sahiner , U.M .Sackesen , C.Erzurum , S.Kalayci, 5 , 9 ? 19CrossRef ] [ PubMed, , 2012

58. Ethanol oxidation and toxicity : role of alcohol P ? 450 oxygenase, Koop DRCoon MJ, Alcohol Clin . Exp . Res10 : 44S-49S, , 1986

59. Molecular Mechanism of Alcoholic Fatty Liver . Indian J. Pharmacol, Rasineni , K.Casey , C.A, 44 , 299 ? 303 . [ CrossRef ] [ PubMed, , 2012

60. S. Overview : How Is Alcohol Metabolized by the Body ? Alcohol Res, Zakhari, Health29 , 245 ? 254, , 2006

61. Oxidative injury and potential use of antioxidants in schizophrenia, Mahadik SPScheffer RE, Prostaglandins Leukot . Essent . Fatty Acids 55 : 45-54, , 1996

62. Role of ethanol in the regulation of hepatic stellate cell function, Wang JBatey RGGeorge J, World J. Gastroenterol . 12 : 6926-6932, , 2006

63. Targeting inflammation for the treatment of alcoholic liver disease, Xu MJZhou ZParker RGao B, Pharmacol . Ther180 : 77-89, , 2017

64. Selected species of edible insects as a source of nutrient composition, ska EBaraniak BKara ? Mska KJakubczyk A, Food Res . Int . 77 : 460-466, , 2015

65. , B. Enteric Dysbiosis Associated with a Mouse Model of Alcoholic Liver, , A.W; Fouts , D.E; Brandl ,? rkel ,; Torralba ,; Schott ,; Tsukamoto ,; Nelson , K.E; Brenner , D.A;, ., 53 , 96 ? 105 . [, , Hepatology

66. 5th editionSection 30.5 , ethanol alters energy metabolism in the liver, Berg , JMTymoczko , JL , StryerL. Biochemistry, New York : W H Freeman, , 2002

67. N. Importance and Regulation of Hepatic Glutathione . Semin . Liver Dis, Deleve , L.D .Kaplowitz, 10 , 251 ? 266CrossRef ] [ PubMed, , 1990

68. Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP, Xu XSo JSPark JGLee AH, Semin . Liver Dis . 33 : 301-311, , 20132013

69. A proposed model of fat packaging by exchangeable lipid droplet proteins, Wolins NEBrasaemle DLBickel PE, FEBS Lett580 : 5484-5491, , 2006

70. Fukui H. The effect of inflammatory cytokines in alcoholic liver disease, Kawaratani HTsujimoto TDouhara ATakaya HMoriya KNamisaki TNoguchi RYoshiji HFujimoto M, Mediators . Inflamm . 2013 : 495156, , 2013

71. Marination and fermentation of yellow mealworm larvae ( Tenebrio molitor, Borremans ALenaerts SCrauwels SLievens BVan Campenhout L., Food Control 92 : 47-52, , 2018

72. Nutritional composition of five commercial edible insects in South Korea, Ghosh SLee SMJung CMeyer-Rochow VB, J. Asia Pac . Entomol . 20 : 686-694, , 2017

73. Vantomme P. Edible insects : Future prospects for food and feed security, Huis AVItterbeeck JVKlunder HMertens EHalloran AMuir G, , 2013

74. Herbal medicines for the prevention of alcoholic liver disease : a review, Ding RBTian KHe CWJiang YWang YTWan JB, J. Ethnopharmacol . 144 : 457-465, , 2012

75. Bataller R. Trends in the management and burden of alcoholic liver disease, Mathurin P, J. Hepatol62 : S38-S46, , 2015

76. Behavior of oxidative stress markers in alcoholic liver cirrhosis patients, Galicia-Moreno MRosique-Oramas DMedina-Avila ZAlvarez-Torres TFalcon Djar YLCordero-Perez Poz-Espinosa Lndez JLKershenobich D, Oxid . Med . Cell Longev, , 20162016

77. Treatment of alcohol use disorder in patients with alcoholic liver disease, Leggio LLee MR, Am . J. Med130 : 124-134, , 2017

78. Trends in alcoholic liver disease research-clinical and scientific aspects, Mandrekar , PAmbade , A ., Cellular signaling pathways in alcoholic liver disease . p 91-112, , 2012

79. ; Liu , Y. ; Guo , R.C . Anti-Tumor Effect of Paeonol via Regulating NF-κB, . Wu ,; Xue , X.Wu , Z.Zhao , H.L .Cao , H.M. ;, D.Q .Wang , R.M; Sun ,, AKT and MAPKs Activation :. Biomed . Prev . Nutr . 2014, , Quick

80. T. Effect of Alanine on D-Galactosamine-Induced Acute Liver Failure in Rats, Maezono , K.Mawatari , K.Kajiwara , K.Shinkai , A.Maki, Hepatology24 , 1211 ? 1216, , 1996

81. U.K. Hepatic Free Fatty Acids in Alcoholic Liver Disease and Morbid Obesity, Mavrelis , P.G .Ammon , H.V .Gleysteen , J.J.Komorowski , R.A.Charaf, HepatologyCrossRef ] Metabolites10 , 436 15 of 16, , 19832020

82. A.H. Transcriptional Control of Hepatic Lipid Metabolism by SREBP and ChREBP, Xu , X.So , J.S .Park , J.G .Lee, Semin . Liver Dis33 , 301 ? 311 . [ CrossRef, , 2013

83. E. A Specific Amino Acid Formula Prevents Alcoholic Liver Disease in Rodents, Tedesco , L.Corsetti , G.Ruocco , C.Ragni , M.Rossi , F.Carruba , M.O .Valerio , A.Nisoli, Am . J. Physiol . Gastrointest . Liver Physiol314 , G566 ? G582 . [ CrossRef ] [ PubMed, , 2018

84. Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length, Park WJPark JWMerrill Jr AHStorch JPewzner-Jung YFuterman AH, Biochim . BiophysActa . 1841 : 1754-1766, , 2014

85. Hepatic glutathione reductase I. Purification and general kinetic properties, Mize CELangdon RG, J. Biol . Chem237 : 1589-1595 . 1962,

86. Redox control of asthma : molecular mechanisms and therapeutic opportunities, Comhair SAErzurum SC, Antioxid . Redox Signal . 12 : 93-124, , 2010

87. , C. ; Kang , J.X . ; Liu , B. ; Wan , J. Omega-3 Polyunsaturated Fatty Acids, . Wang , M.Zhang , X.Ma , L.J; Feng ,. ; Yan ,; Su ,;, Ethanol-Induced Adipose HyperlipolysisA Mechanism for Hepatoprotective EffectDisease . Biochim . Biophys . Acta Mol, , Alcoholic

88. , M.J. Metabolomic Study of Aging in Mouse Plasma by Gas Chromatography ? Mass, . Seo ,; Hwang , Y.H; Kim ,; Joo , B.S; Yee , S.T; Kim , C.M;, . J. Chromatogr . B Analyt . Technol . Biomed . Life, 1025 , 1 ? 6 . [, , .

89. Bataller R. Alcoholic liver disease : pathogenesis and new therapeutic targets, Gao B, Gastroenterology141 : 1572-1585, , 2011

90. Lee , M.O . ; Lee , B.H . Differential Gene Expression and Lipid Metabolism in, 37 ., H.Q . ;, M.G .Kim , J.H .Kong , G. ;, K.S . ;, H.L . ;, B.I ., Liver Induced by Acute Ethanol. Toxicol . Appl . Pharmacol . 2007, , in

91. Omega-3 and omega-6 polyunsaturated fatty acids : Dietary sources , metabolism, 257 . Saini RKKeum YS, , 2018

92. Seki E. Alcoholic liver disease : a current molecular and clinical perspective, Ohashi KPimienta M, Liver Res . 2 : 161-172, , 2018

93. Edible insects in a food safety and nutritional perspective : a critical review, Belluco SLosasso CMaggioletti MAlonzi CCPaoletti MGRicci A, Compr . Rev . Food SciFood Saf . 12 : 296-313, , 2013

94. Helmrath T. A rapid spectrophotometric assay for carnitine palmitoyltransferase, Bieber LLAbraham T, Anal . Biochem50 : 509-518, , 1972

95. Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2, Lee YKPark JELee MHardwick JP, Liver Res . 2 : 209-215, , 2018

96. entomophagy and processing into ready to use therapeutic ingredients : a review, Feng S. Tenebrio molitor L., J. Nutr . Health Food Eng8 , 280 ? 285 . [ CrossRef, , 2018

97. ; Xie , Q. ; Pan , X.P . ; Xu , W. ; Yuan , W.X . ; et al . A Serum Metabonomics, J.S . ; LiuW. ; HaoS.R . ; GuoY.Z . ;, H.J . ;, on the Difference Between Alcohol-andby Ultraperformance Liquid Chromatography Coupled, , Liver

98. Effects of ethanol on the metabolism of free fatty acids in isolated liver cells, Ontko JA, J. Lipid Res . 14 : 78-86, , 1973

99. Protective effects of sericin protein on alcohol ? mediated liver damage in mice, Li YGJi DFChen SHu GY, Alcohol Alcohol 43 : 246-253, , 2008

100. A.H. Hepatic Fatty Acid Uptake Is Regulated by the Sphingolipid Acyl Chain Length, Park , W.J .Park , J.W .Merrill Jr , A.H.Storch , J.Pewzner-Jung , Y.Futerman, Biochim . BiophysActa1841 , 1754 ? 1766 . [ CrossRef ] [ PubMed, , 2014

101. Chae S. Beneficial effects of insect extracts on nonalcoholic fatty liver disease, Lee JYIm ARShim KSJi KYKim KMKim YH, J. MedFood 23 : 760-771, , 2020

102. Chronic liver inflammation : clinical implications beyond alcoholic liver disease, Park BJLee YJLee HR, World J. Gastroenterol . 20 : 2168-2175, , 2014

103. Glutathione S-transferases the first enzymatic step in mercapturic acid formation, Habig WHPabst MJJakoby WB, J. Biol . Chem249 : 7130-7139, , 1974

104. Linking pathogenic mechanisms of alcoholic liver disease with clinical phenotypes, 225 . Nagy LEDing WXCresci GSaikia PShah VH, Gastroenterology150 : 1756- 1768, , 2016

105. Regulatory effects of Tenebrio molitor Linnaeus on immunological function in mice, Tang QDai YZhou B, Afr . J. Biotechnol . 11 : 8348-8352, , 2012

106. The ameliorative effect of Protaetia brevitarsis larvae in HFD-induced obese mice, Ahn EMMyung NYJung HAKim SJ, Food SciBiotechnol . 28 : 1177- 1186, , 2019

107. , Y.R . ; Bae , S.H . ; Jang , J.Y . ; Kim , D.Y . ; Lee , J.S . ; et al . Effects, 8 . Park ,. ; Tak ,. ; Park ,. ; Kweon ,. ; Jang ,, Branched-Chain Amino Acidson the Progression of Advanced Liver, , BCAAs

108. Cautiously Using Natural Medicine to Treat Liver Problems . World J. Gastroenterol, Xiong , F.Guan , Y.S, 23 , 3388 ? 3395 . [ CrossRef ] [ PubMed, , 2017

109. Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice, Yin MWheeler MDKono HBradford BUGallucci RMLuster MIThurman RG, Gastroenterology117 : 942-952, , 1999

110. Metabolism of dietary stearic acid relative to other fatty acids in human subjects, Emken EA, Am . J. Clin . Nutr . 60 : 1023S-1028S, , 1994

111. Targeting hepatic glycerolipid synthesis and turnover to treat fatty liver disease, Schweitzer GGFinck BN, Advances in Hepatology 2014 : 1-14, , 2014

112. The latest updates on the medical treatment of alcoholic hepatitis you should know, Jang JY, Korea J. Med575-579, , 20182018

113. Fatty acid synthesis by rat liver after chronic ethanol feeding with a low-fat diet, Simpson KJVenkatesan SPeters TJ, Clin . Sci87 : 441-446, , 1994

114. Nisoli E. A specific amino acid formula prevents alcoholic liver disease in rodents, Tedesco LCorsetti GRuocco CRagni MRossi FCarruba MOValerio A, Am . J. PhysiolGastrointest . Liver Physiol . 314 : G566-G582, , 2018

115. Recent insights into the biological functions of liver fatty acid binding protein 1, Wang GBonkovsky HLde Lemos ABurczynski FJ, J. Lipid Res56 : 2238- 2247, , 2015

116. al . β-Hydroxybutyrate Protects from Alcohol-Induced Liver Injury via a Hcar2-cAMP, 28 . ChenY. ; OuyangX. ; HoqueR. ; Garcia-MartinezI. ; Yousaf ,. ; TonackS. ; OffermannsS. ; DubuquoyL. ; LouvetA. ; Mathurin, Pathway .2018 , 69 , 687 ? 696 ., , Hepatol

117. A. Transcriptional Regulation of Acyl-CoA : Glycerol-sn-3-Phosphate Acyltransferases, Karasawa , K.Tanigawa , K.Harada , A.Yamashita, Int . J. Mol20 , E964 . [ CrossRef, , 2019

118. Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis, Lee JJLambert JEHovhannisyan YRamos-Roman MATrombold JRWagner DAParks EJ, Am . J. Clin . Nutr . 101 : 34-43, , 2015

119. Alcohol induces more severe fatty liver disease by influencing cholesterol metabolism, Li BLei SSSu JCai XMXu HHe XChen YHLu HXLi HQian LQ, Evid . Based . Complement . Alternat . Med7095684, , 20192019

120. Schnabl B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease, Yan AWE. Fouts DBrandl Jrkel PTorralba MSchott ETsukamoto HE. Nelson KA. Brenner D, Hepatology 53 : 96-105, , 2011

121. Schnabl B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease, Yan AWFouts DEBrandl Jrkel PTorralba MSchott ETsukamoto HNelson KEBrenner DA, Hepatology 53 : 96-105, , 2011

122. A Simple Method for the Isolation and Purification of Total Lipids from Animal Tissues, Folch , J.Lees , M.Sloane-Stanley , G.H, J. Biol . Chem . 1957226 , 497 ? 509,

123. Effects of prolonged ethanol intake : production of fatty liver despite adequate diets, Lieber CSJones DPDeCarli LM, J. Clin . Invest44 : 1009-1021, , 1965

124. Metabolomics : An Emerging but Powerful Tool for Precision Medicine . Cold Spring Harb, Clish , C.B, Mol . Case Stud1 , a000588 . [ CrossRef, , 2015

125. Y. Probiotic and Glutamine Treatments Attenuate Alcoholic Liver Disease in a Rat Model, Huang , H.Lin , Z.Zeng , Y.Lin , X.Zhang, Exp . Ther18 , 4733 ? 4739 . [ CrossRef ] [ PubMed, , 2019

126. A simple method for the isolation and purification of total lipides from animal tissues, Folch JLees MStanley GS, J. Biol . Chem226 : 497-509 . 1957,

127. The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases, Soares JBPimentel-Nunes PRoncon-Albuquerque RLeite-Moreira A, Hepatol .Int . 4 : 659-672, , 2010

128. Grunfeld C. Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo, 214 . Feingold KR, J. Clin . Invest80 : 184-190, , 1987

129. extract improves insulin sensitivity and alleviates hyperglycemia in C57BL/Ksj-db/db Mice, Kim SYPark JEHan JSTenebrio molitor, J . Life . Sci29 : 570-579, , 2019

130. Dose Response of Ethanol on Antioxidant Defense System of Liver , Lung , and Kidney in Rat, Scott , R.B .Reddy , K.S .Husain , K.Schlorff , E.C .Rybak , L.P.Somani , S.M, PathophysiologyCrossRef ] Nutrients12 , 1426 15 of 15, , 20002020

131. Dose response of ethanol on antioxidant defense system of liver , lung , and kidney in rat, 233 . Scott RBReddy KSHusain KSchlorff ECRybak LPSomani SM, Pathophysiology 7 : 25-32, , 2000

132. Majumder K. Food-derived bioactive peptides in human health : challenges and opportunities, Chakrabarti SGuha S, Nutrients 10 : 1738, , 2018

133. Multi-Dimensional Roles of Ketone Bodies in Fuel Metabolism , Signaling , and Therapeutics, Puchalska , P.Crawford , P.A, Cell Metab25 , 262 ? 284 . [ CrossRef, , 2017

134. Could defatted mealworm ( Tenebrio molitor ) and mealworm oil be Used as food ingredients ?, Son YJChoi SYHwang IKNho CWKim SH, Foods 9 : 40, , 2020

135. Hepatic lipid accumulation : cause and consequence of dysregulated glucoregulatory hormones, 209 . Geisler CERenquist BJ, J. Endocrinol . 234 : R1-R21, , 2017

136. P. The Link between Inflammation , Bugs , the Intestine and the Brain in Alcohol Dependence, Leclercq , S.de Timary , P.Delzenne , N.M., Transl . Psychiatry7 , e1048 . [ CrossRef ] [ PubMed, , 2017

137. Sawant A. Oxidative stress and antioxidative status in patients with alcoholic liver disease, 239 . Shinde AGanu JNaik P, Biomed . Res23 : 105-108, , 2012

138. Tenebrio molitor Larvae ) as an alternative protein source for monogastric animal : a review, Hong JHan TKim YY . Mealworm, Animals 10 : 2068, , 2020

139. Zhang Y. Probiotic and glutamine treatments attenuate alcoholic liver disease in a rat model, Huang HLin ZZeng YLin X, Exp . Ther . Med18 : 4733-4739, , 2019

140. A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-α production, Zhou ZWang LSong ZLambert JCMcClain CJKang YJ, Am . J. Pathol163 : 1137-1146, , 2003

141. The gastrointestinal microbiome : alcohol effects on the composition of intestinal microbiota, Engen PAGreen SJVoigt RMForsyth CBKeshavarzian A, Alcohol Res37 : 223, , 2015

142. Anti-tumor effect of paeonol via regulating NF-κB , AKT and MAPKs activation : a quick review, Wu JXue XWu ZZhao HLCao HMSun DQWang RMSun JLiu YGuo RC, Biomed . Prev . Nutr . 4 : 9-14, , 2014

143. CD36-deficient mice are resistant to alcohol-and high-carbohydrate ? induced hepatic steatosis, Clugston RDYuen JJHu YAbumrad NABerk PDGoldberg IJBlaner WSHuang LS, J. Lipid Res . 55 : 239-246, , 2014

144. Dietary macronutrient composition determines the contribution of DGAT 1 to alcoholic steatosis, Huang LSYuen JJTrites MJSaha AEpps CTHu YKerolle SLee SAJiang HGoldberg IJ, Alcohol . Clin . Exp . Res42 : 2298- 2312, , 2018

145. S ? nchez-P ? rez PLamas S. Antioxidant responses and cellular adjustments to oxidative stress, Espinosa-Diez CMiguel VMennerich DKietzmann TCadenas S, Redox Biol . 6 : 183-197, , 2015

146. Therapeutic effects of amino acids in liver diseases : current studies and future perspectives, Lee DYKim EH, J . Cancer Prev24 , 72 ? 78 . [ CrossRef ] [ PubMed, , 2019

147. Yamashita A. Transcriptional regulation of acyl-CoA : glycerol-sn-3-phosphate acyltransferases, Karasawa KTanigawa KHarada A, Int . J. Mol . Sci20 : E964, , 2019

148. ; Lee , H.I . ; et al . Defatted Tenebrio molitor Larva Fermentation Extract Modifies Steatosis, Choi , R.Y .Ham , J.R.Ryu , H.S .Lee , S.S.Miguel , M.A; Paik , M.J.Ji , M. ;, K.W . ;, InflammationMicroflora in Chronic Alcohol-Fed Rats ., , and

149. I. Pyroglutamic Acidosis as a Cause for High Anion Gap Metabolic Acidosis : A Prospective Study, Spector , S.R .Mayan , H.Loebstein , R.Markovits , N.Priel , E.Massalha , E.Shafir , Y.Gueta, Sci . Rep.9 , 3554 . [ CrossRef ] [ PubMed, , 2019

150. Reue K. How lipid droplets “ TAG ” along : glycerolipid synthetic enzymes and lipid storage, 203 . Wang HAirola MV, Biochim . BiophysActa . 1862 : 1131-1145, , 2017

151. Sabench , F. ; Hernandez , M. ; del Castillo , D. Mapping of the Circulating Metabolome Reveals, . Rodr ?, E. ;, M. ;, M. ;, A. ;, R. ;, S. ;, R., as a Predictor ofFatty Liver Disease . IntObes . 2015 ,, , Obesity-Associated

152. Novel hepatoprotective peptides derived from protein hydrolysates of mealworm ( Tenebrio molitor, Cho HRLee SO, Food Res . Int133 , 109194 . [ CrossRef, , 2020

153. The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract, Derrien MCollado MCBen-Amor KSalminen Sde Vos WM, Appl . Environ . Microbiol74 : 1646-1648, , 2008

154. Iron-catalyzed hydroxyl radical formation . Stringent requirement for free iron coordination site, Graf EMahoney JRBryant RGEaton JW, J. Biol . Chem259 : 3620-3624, , 1984

155. Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat, Wheeler MDNakagami MBradford BUUesugi TMason RPConnor HDDikalova AKadiiska MThurman RG, J. Biol . Chem . 276 : 36664-36672, , 2001

156. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease, Grander CAdolph TEWieser VLowe PWrzosek LGyongyosi BWard DVGrabherr FGerner RRPfister A, Gut .67 : 891-901, , 2018

157. Z. Dietary Nicotinic Acid Supplementation Ameliorates Chronic Alcohol-Induced Fatty Liver in Rats, Li , Q.Xie , G.Zhang , W.Zhong , W.Sun , X.Tan , X.Sun , X.Jia , W.Zhou, Alcohol . Clin . Exp . Res38CrossRef ], , 1982

158. ; Bae , S.H . ; Jang , J.Y . ; Kim , D.Y . ; Lee , J.S . ; et al . Effects of Branched-Chain Amino, 26 ., J.G . ;, W.Y . ;, S.Y . ;, Y.O . ;, S.Y . ;, on the Progression of Advanced Liver, , BCAAs

159. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase, Paglia DEValentine WN, J . Lab . Clin . Med70 : 158- 169, , 1967

160. Hekimi S. Superoxide dismutases : dual roles in controlling ROS damage and regulating ROS signaling, Wang YBranicky RNo ? A, J . Cell Biol217 : 1915-1928, , 2018

161. Koivusalo M. Different forms of rat liver aldehyde dehydrogenase and their subcellular distribution, Koivula T, Biochim . BiophysActa . 397 : 9-23, , 1975

162. The effects of defatted Tenebrio molitor larva ferment extract on CCl4-induced liver damage in mice, Choi RYHam JRRyu HSPark KWKang KYLee MK, J. Korean Soc . Food Sci . Nutr48 , 501 ? 508 . [ CrossRef, , 2019

163. Analysis of relative gene expression data using real-time quantitative PCR and the 2-△△CT method, Livak KJSchmittgen TD, Methods25 , 402 ? 408 . [ CrossRef, , 2001

164. E. GC-MS-Based Metabolomics Reveals Mechanism of Action for Hydrazine Induced Hepatotoxicity in Rats, Bando , K.Kunimatsu , T.Sakai , J.Kimura , J.Funabashi , H.Seki , T.Bamba , T.Fukusaki, J. Appl . Toxicol31 , 524 ? 535 . [ CrossRef, , 2011

165. Fatty acid synthesis and triacylglycerol accumulation in rat liver after chronic ethanol consumption, Venkatesan SWard RJPeters TJ, Clin . Sci73 : 159-163, , 1987

166. Kilpatrick L. Cytokines inhibit fatty acid oxidation in isolated rat hepatocytes : synergy among TNF, Nachiappan VCurtiss DCorkey BE, IL-6 , and IL-1 . Shock . 1 : 123-129, , 1994

167. Peroxiredoxin IIIa mitochondrion-specific peroxidase , regulates apoptotic signaling by mitochondria, Chang TSCho CSPark SYu SKang SWRhee SG, J. Biol . Chem279 : 41975-41984, , 2004

168. Polyunsaturated fatty acid deficiency reverses effects of alcohol on mitochondrial energy metabolism, Piquet MARoulet MNogueira VFilippi CSibille BHourmand-Ollivier IPilet MRouleau VLeverve XM, J. Hepatol41 , 721 ? 729 . [ CrossRef, , 2004

169. Gueta I. Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis : a prospective study, Spector SRMayan HLoebstein RMarkovits NPriel EMassalha EShafir Y, Sci .Rep. 9 : 1-4, , 2019

170. R. Impact of Supplementary Amino Acids , Micronutrients , and Overall Diet on Glutathione Homeostasis, Gould , R.L .Pazdro, Nutrients11 , E1056 . [ CrossRef, , 2019

171. Sadana P. Signal transduction mechanisms of alcoholic fatty liver disease : emer ging role of lipin-1, You MJogasuria ALee KWu JZhang YKwang Lee Y, Curr . Mol . Pharmacol10 : 226-236, , 2017

172. St ? rkel P. The link between inflammation , bugs , the intestine and the brain in alcohol dependence, Leclercq Sde Timary PDelzenne NM, Transl . Psychiatry . 7 : e1048, , 2017

173. W. New Concepts of Cellular Fatty Acid Uptake : Role of Fatty Acid Transport Proteins and of Caveolae, Pohl , J.Ring , A.Herrmann , T.Stremmel, Proc . Nutr . Soc63 , 259 ? 262 . [ CrossRef ] [ PubMed, , 2004

174. A . Targeted Deletion of FATP5 Reveals Multiple Functions in Liver Metabolism : Alterations in Hepatic, 45 . DoegeH. ; BaillieR.A. ; OrtegonA.M. ; TsangB. ; WuQ. ; PunreddyS. ; HirschD. ; WatsonN. ; Gimeno ,. ; Stahl, Homeostasis2006 , 130 , 1245 ? 1258 ., , .

175. Analysis of relative gene expression data using real ? time quantitative PCR and the 2 ? ΔΔCT method, Livak KJSchmittgen TD, Methods 25 : 402-408, , 2001

176. Diurnal and dietary ? induced changes in cholesterol synthesis correlate with levels of mRNA for HMG ?, Jurevics HHostettler JBarrett CMorell PToews AD, CoA reductase . J. Lipid Res . 41 : 1048-1053, , 2000

177. Protective Effect of Selected Amino Acids and Food Extracts on Ethanol Toxicity Decrement in Rat Liver, Lee , J.H .Kim , N.K .Lee , D.Y .Lee , C.H, Korean J . Food Sci . Technol31 , 802 ? 808 . Nutrients12 , 1426 14 of 15, , 19992020

178. Protective effect of selected amino acids and food extracts on ethanol toxicity decrement in rat liver, Lee JHKim NKLee DYLee CH, Korean J . Food Sci . Technol31 : 802-808, , 1999

179. Stahl A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase, Falcon ADoege HFluitt ATsang BWatson NKay MA, Am . J. Physiol . Endocrinol . Metab . 299 : E384-E393, , 2010

180. Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism , signaling , and therapeutics, 243 . Puchalska P, Cell Metab25 : 262-284, , 2017

181. L. Differential Metabolic Pathways and Metabolites in a C57BL/6J Mouse Model of Alcoholic Liver Disease, Ma , T.Li , Y.Zhu , Y.Jiang , S.Cheng , C.Peng , Z.Xu, Med . Sci . Monit26 , e924602 . [ CrossRef, , 2020

182. Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease ( NAFLD ), Musso GGambino R, Prog . Lipid Res . 48 : 1-26, , 2009

183. Schl ? ter OK . Potential and challenges of insects as an innovative source for food and feed production, Rumpold BA, Innov . Food SciEmerg . Technol17 , 1 ? 11 . [ CrossRef, , 2013

184. X. ; Yin , X. ; Sun , X. ; Kim , S. Chronic Alcohol Exposure Stimulates Adipose Tissue Lipolysis in Mice, Zhong , W.Zhao , Y.Tang , Y.Wei , X.Shi , X.Sun , W.Sun, Role of Reverse TriglyceridePathogenesis of Alcoholic Steatosis . Am . J. Pathol . 2012, , in

185. Zhou Z. Dietary nicotinic acid supplementation ameliorates chronic alcohol ? induced fatty liver in rats, Li QXie GZhang WZhong WSun XTan XSun XJia W, Alcohol Clin . Exp . Res38 : 1982-1992, , 2014

186. , R. Essential Amino Acid Supplementation Decreases Liver Damage Induced by Chronic Ethanol Consumption in, . Corsetti ,; Stacchiotti ,; Tedesco ,; D ’,; Pasini ,; Dioguardi ,; Nisoli ,;, . Int . J., 24 , 611 ? 619 . [ CrossRef ] [, , .

187. Chae S. Hepatoprotective effects of insect extracts in an animal model of nonalcoholic fatty liver disease, Im ARYang WKPark YCKim SH, Nutrients 10 : 735, , 2018

188. Evaluation of genotoxicity and 28-day oral dose toxicity on freeze-dried powder of Tenebrio molitor larvae, Han SRYun EYKim JYHwang JSJeong EJMoon KS, yellow mealworm ) . Toxicol . Res . 30 : 121-130, , 2014

189. Ferrous ion oxidation in presence of ferric ion indicator xylenol orange for measurement of hydroperoxides, Wolff SP, Meth . Enzymol . 233 : 182-189, , 1994

190. Omega-3 and Omega-6 Polyunsaturated Fatty Acids : Dietary Sources , Metabolism , and Significance-A Review, Saini , R.K.Keum , Y.S, Life Sci203 , 255 ? 267CrossRef ] [ PubMed, , 2018

191. Personal Care Compositions with Glutathione Precursor Comprising 4-Substituted Resorcinols and Amino Acids, Guelakis , M.P .Lee , J.Rosa , J.G .Madison , S.A.Damodaran , A.Kumari , A.Huang , N.Harichian , B, USA Patent PCT/CN2017/116999 , 28Metabolites10 , 436 16 of 16, , 2020

192. Personal care compositions with glutathione precursor comprising 4-substituted resorcinols and amino acids, Guelakis MPLee JRosa JGMadison SADamodaran AKumari AHuang NHarichian B, USA Patent PCT/CN2017/116999, , 202028 June 2018

193. Xu L. Differential metabolic pathways and metabolites in a C57BL/6J Mouse model of alcoholic liver disease, Ma TLi YZhu YJiang SCheng CPeng Z, Med . Sci . Monit26 : e924602, , 2020

194. Anti-steatotic and anti-inflammatory effects of Hovenia dulcis Thunb . extracts in chronic alcohol-fed rats, Choi RYWoo MJHam JRLee MK, Biomed . Pharmacother90 , 393 ? 401 . [ CrossRef, , 2017

195. Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice, 193 . Yin HQKim MGKim JHKong GKang KSKim HLYoon BILee MOLee BH, Toxicol . Appl . Pharmacol . 223 : 225-233, , 2007

196. Global Burden of Disease and Injury and Economic Cost Attributable to Alcohol Use and Alcohol-Use Disorders, Rehm , J.Mathers , C.Popova , S.Thavorncharoensap , M.Teerawattananon , Y.Patra , J, Lancet373 , 2223 ? 2233 . [ CrossRef, , 2009

197. Mathurin P. β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway, Chen YOuyang XHoque RGarcia-Martinez IYousaf MNTonack SOffermanns SDubuquoy LLouvet A, J. Hepatol69 : 687-696, , 2018

198. Pazdro R. Impact of Supplementary Amino Acids , Micronutrients , and Overall Diet on Glutathione Homeostasis, 234 . Gould RL, Nutrients 11 : E1056, , 2019

199. Possmayer F. The role of Mg2-dependent phosphatidate phosphohydrolase in pulmonary glycerolipid biosynthesis, Walton PA, Biochim . BiophysActa . 796 : 364-372, , 1984

200. Adipose differentiation ? related protein is a reliable lipid droplet marker in alcoholic fatty liver of rats, Mak KMRen CPonomarenko ACao QLieber CS, Alcohol Clin . Exp . Res32 , 683 ? 689 . [ CrossRef, , 2008

201. Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol : a targeted lipidomic and gene expression study, Clugston RDJiang HLee MXPiantedosi RYuen JJRamakrishnan RLewis MJGottesman MEHuang LGoldberg IJ, J. Lipid Res52 : 2021-2031, , 2011

202. Lipid droplet-associated proteins in alcoholic liver disease : a potential linkage with hepatocellular damage, Ikura YCaldwell SH, Int . J. Clin . Exp . Pathol8 : 8699-8708, , 2015

203. zquez-Guti ? rrez JLLangton M. Yellow mealworm protein for food purposes-extraction and functional properties, Zhao X , VJohansson DPLandberg R, PLoS One11 : e0147791, , 2016

204. Airway microbial diversity is inversely associated with mite-sensitized rhinitis and asthma in early childhood, Chiu CYChan YLTsai YSChen SAWang CJChen KFChung IF, Sci . Rep.7 , 1 . [ CrossRef ] [ PubMed, , 2017

205. O ’ Connor JBAlcoholic liver disease : proposed recommendations for the American college of Gastroenterology, McCullough AJ, Am . J. Gastroenterol . 93 : 2022-2036, , 1998

206. Stremmel W. New concepts of cellular fatty acid uptake : role of fatty acid transport proteins and of caveolae, Pohl JRing AHerrmann T, Proc . Nutr . Soc63 : 259-262, , 2004

207. Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage ? mediated chronic inflammation, Sunami Yuser FGul SFiedler KG ? ldiken NEspenlaub SHolzmann KHipp NSindrilaru ALuedde T, Hepatology 56 : 1117-1128, , 2012

208. M.J. Metabolomic Study of Polyamines in Rat Urine following Intraperitoneal Injection of γ-Hydroxybutyric Acid, Lee , H.S .Seo , C.Kim , Y.A .Park , M.Choi , B.Ji , M.Lee , S.Paik, Metabolomics15 , 58 . [ CrossRef, , 2019

209. ; Gai , F. ; Rotolo , L. ; Belforti , M. ; Bergero , D. ; Katz , H. ; Dabbou , S. ; et al . Nutritional Value of, . De MarcoM. ; Martnez , S.Hernandez , F., Insect Larval Meals () for Broiler Chickens : Apparent Nutrient Digestibility, , Hermetia

210. Devaki T. Hepatoprotective effect of allicin on tissue defense system in galactosamine/endotoxin challenged rats, Vimal V, J. Ethnopharmacol . 90 : 151-154, , 2004

211. Edible Insects as a Protein Source : A Review of Public Perception , Processing Technology , and Research Trends, Kim , T.K .Yong , H.I .Kim , Y.B .Kim , H.W .Choi , Y.S, 39 , 521 ? 540CrossRef ] [ PubMed, , 2019

212. Hepatocyte ? specific disruption of CD36 attenuates fatty liver and improves insulin sensitivity in HFD-fed mice, Wilson CGTran JLErion DMVera NBFebbraio MWeiss EJ, Endocrinology 157 : 570-585, , 2016

213. Influence of Alcohol Consumption on Body Mass Gain and Liver Antioxidant Defense in Adolescent Growing Male Rats, Kołota , A.Gł ˛abska , D.Oczkowski , M.Gromadzka-Ostrowska , J, Int . J. Environ . Res . Public Health16 , 2320 . [ CrossRef, , 2019

214. Influence of alcohol consumption on body mass gain and liver antioxidant defense in adolescent growing male rats, Kołota Abska DOczkowski MGromadzka-Ostrowska J, Int . J. Environ . Res . Public Health16 : 2320, , 2019

215. Mapping of glutathione and its precursor amino acids reveals a role for GLYT2 in glycine uptake in the lens core, Lim JLi LJacobs MDKistler JDonaldson PJ, Investig . Ophthalmol . Vis . Sci48 , 5142 ? 5151 . [ CrossRef ] [ PubMed, , 2007

216. ; Fritz , K.S . Investigating RNA Expression Profiles Altered by Nicotinamide Mononucleotide Therapy in a Chronic, Assiri , M.A .Ali , H.R .Marentette , J.O; Yun ,; Liu , J.Hirschey , M.D .Saba , L.M .Harris , P.S, of Alcoholic Liver. Genom . 2019 , 13, , .

217. Assessment of antioxidant properties of membrane ultrafiltration peptides from mungbean meal protein hydrolysates, Sonklin CLaohakunjit NKerdchoechuen O, PeerJ . 6 : e5337, , 2018

218. Fukusaki E. GC ? MS ? based metabolomics reveals mechanism of action for hydrazine induced hepatotoxicity in rats, Bando KKunimatsu TSakai JKimura JFunabashi HSeki TBamba T, J. Appl . Toxicol . 31 : 524-535, , 2011

219. Protective effect of Pyropia yezoensis glycoprotein on chronic ethanol consumption-induced hepatotoxicity in rats, Choi JWKim IHKim YMLee MKChoi YHNam TJ, Mol . MedRep. 14 : 4881-4886, , 2016

220. , J. ; et al . Metagenomic Analyses of Alcohol Induced Pathogenic Alterations in the Intestinal Microbiome and the, 60 . Bull-OttersonL. ; FengW. ; KirpichI. ; WangY. ; QinX. ; LiuY. ; GobejishviliL. ; Joshi-BarveS. ; Ayvaz, of LactobacillusTreatment . PLoS ONE 2013 ,, , rhamnosus

221. ACAT-2 , a second mammalian acyl-CoA : cholesterol acyltransferase its cloning , expression , and characterization, Cases SNovak SZheng YMyers HMLear SRSande EWelch CBLusis AJSpencer TAKrause BR, J. Biol . Chem273 : 26755-26764, , 1998

222. Improvement effect of fermented silkworm ( Bombyx mori L. ) powder against orotic acid-induced fatty liver in rats, Ahn HYCha JYPark KRKim YRCho YS, J . Life Sci23 : 789-795, , 2013

223. M. Enzymatic Hydrolysis of Insect Alphitobius diaperinus towards the Development of Bioactive Peptide Hydrolysates, Sousa , P.Borges , S.Pintado, Food Funct11 , 3539 ? 3548 . [ CrossRef ] [ PubMed, , 2020

224. S.M . ; Lee , M.K . Effect of Curcumin Supplementation on Blood Glucose , Plasma Insulin , and Glucose Homeostasis, 31 . Seo ,. ; Choi ,. ; Jung ,. ; Kim ,. ; Yeo ,. ; Jeon, Enzyme Activities in Diabetic db/db MiceNutr . Food Res . 2008 , 52 ,, , Mol

225. ; et al . Antihypertensive , Cardio-and Neuro-Protective Effects of Tenebrio molitor ( Coleoptera : Tenebrionidae ), 6 . PessinaF. ; FrosiniM. ; MarcolongoP. ; FusiF. ; SaponaraS. ; GamberucciA. ; ValotiM. ; GiustariniD. ; Fiorenzani, Larvae inRats . PLoS ONE 2020 ,, , Spontaneously

226. Ameliorative effects of pepsin-digested chicken liver hydrolysates on development of alcoholic fatty livers in mice, Lin YLTai SYChen JWChou CHFu SGChen YC, Food Funct8 , 1763 ? 1774 . [ CrossRef, , 2017

227. Protective Effects of Dietary Glycine and Glutamic Acid toward the Toxic Effects of Oxidized Mustard Oil in Rabbits, Zeb , A.Rahman , S.U, Food Funct8 , 429 ? 436 . [ CrossRef ] [ PubMed, , 2017

228. Schnabl B. Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver disease, Yan AW, World J. Hepatol . 4 : 110-118, , 2012

229. Delivery of the Cu/Zn ? superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats, 222 . Wheeler MDKono HYin MRusyn IFroh MConnor HDMason RPSamulski RJThurman RG, Gastroenterology120 : 1241-1250, , 2001

230. Miyazawa T. Oxidative stress during development of alcoholic fatty liver : therapeutic potential of cacao polyphenol, Suzuki KNakagawa KMiyazawa TKato SKimura FKamei M, Biosci . Biotechnol . Biochem . 77 : 1792-1794, , 2013

231. Preparation of two oligopeptides from corn protein and their protective effect on acute alcohol intoxication in mice, Sun NXu TLiu YYe CJiang ZDu FWang Y, Biomed . Res29 , 1284 ? 1289 . [ CrossRef, , 2018

232. Targeted deletion of FATP5 reveals multiple functions in liver metabolism : alterations in hepatic lipid homeostasis, Doege HBaillie RAOrtegon AMTsang BWu QPunreddy SHirsch DWatson NGimeno REStahl A, Gastroenterology130 : 1245-1258, , 2006

233. Oleic acid and linoleic acid from Tenebrio molitor larvae inhibit BACE1 activity in vitro : molecular docking studies, Youn KJYun EYLee JHKim JYHwang JSJeong WSJun MR., J. Med . Food17 , 284 ? 289 . [ CrossRef, , 2014

234. Rezzani R. Essential amino acid supplementation decreases liver damage induced by chronic ethanol consumption in rats, Corsetti GStacchiotti ATedesco LD'Antona GPasini EDioguardi FSNisoli E, Int . J. Immunopathol . Pharmacol24 : 611- 619, , 2011

235. Shin D. Mealworm larvae ( Tenebrio molitor L. ) exuviae as a novel prebiotic material for BALB/c mouse gut microbiota, Kwon GTYuk HGLee SJChung YHJang HSYoo JSCho KHKong H, Food Sci .Biotechnol . 29 : 531-537, , 2019

236. functional and biological properties of insect proteins : processes for obtaining , consumption and future challenges, RJS de COhara Ados Santos Aguilar JGDomingues MAF . Nutritional, Trends Food Sci . Technol . 76 : 82-89, , 2018

237. Suppression of PPARγ-Mediated Monoacylglycerol O-Acyltransferase 1 Expression Ameliorates Alcoholic Hepatic Steatosis, Yu , J.H .Song , S.J .Kim , A.R .Choi , Y.J .Seok , J.W .Kim , H.J .Lee , Y.J .Lee , K.S .Kim , J.W, Sci . Rep.6 , 29352 . [ CrossRef, , 2016

238. Suppression of PPARγ-mediated monoacylglycerol O-acyltransferase 1 expression ameliorates alcoholic hepatic steatosis, Yu JHSong SJKim AChoi YSeok JWKim HJLee YJLee KSKim JW, Sci .Rep. 6 : 1-12, , 2016

239. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease : mechanisms and pathophysiological role, Aubert JBegriche KKnockaert LRobin MAFromenty B, Clin . Res . Hepatol . Gastroenterol35 : 630-637, , 2011

240. Liu S. Ezetimibe prevents the development of non-alcoholic fatty liver disease induced by high-fat diet in C57BL/6J mice, Wang XRen QWu TGuo YLiang Y, Mol . MedRep. 10 : 2917-2923, , 2014

241. Lee S. Enzymatic preparation and antioxidant activities of protein hydrolysates from Tenebrio molitor larvae ( Mealworm ), Yu MLee HCho H, J. Korean Soc . Food Sci . Nutr . 46 : 435-441, , 2017

242. Paik , M.J . Simultaneous Analysis of Seven 2-Hydroxy Fatty Acids as Tert-Butyldimethylsilyl Derivatives in Plasma by Gas, Seo , C.Yoon , J.Rhee , Y.Kim , J.J. ;, S.J .Lee , W.Lee , G. ;, S.T ., ? Mass SpectrometryChromatogr . 2015 , 29 , 156 ?, , Biomed

243. Specific role for acyl CoA : diacylglycerol acyltransferase 1 ( Dgat1 ) in hepatic steatosis due to exogenous fatty acids, Villanueva CJMonetti MShih MZhou PWatkins SMBhanot SFarese Jr RV, Hepatology 50 : 434-442, , 2009

244. M.J. Metabolomic Analysis of Urinary Organic Acids following Intraperitoneal Injection with γ-Hydroxybutyric Acid in Rats, Seo , C.Park , M.Choi , B.Lee , S.Paik, Metabolomics12 , 190 . [ CrossRef, , 2016

245. Mammalian fatty acid synthase activity from crude tissue lysates tracing 13C-labeled substrates using gas chromatography ?, Rudolph MCMaluf NKWellberg EAJohnson CAMurphy RCAnderson SM, mass spectrometry . Anal . Biochem . 428 : 158- 166, , 2012

246. M.J. Metabolomic Screening and Star Pattern Recognition by Urinary Amino Acid Profile Analysis from Bladder Cancer Patients, Kim , J.W .Lee , G.Moon , S.M .Park , M.J.Hong , S.K .Ahn , Y.H .Kim , K.R .Paik, Metabolomics6 , 202 ? 206 . [ CrossRef, , 2010

247. Metabolomic Profiling Reveals Novel Biomarkers of Alcohol Intake and Alcohol-Induced Liver Injury in Community-Dwelling Men, Harada , S.Takebayashi , T.Kurihara , A.Akiyama , M.Suzuki , A.Hatakeyama , Y.Sugiyama , D.Kuwabara , K.Takeuchi , A.Okamura , T., Phytomedicine74 , 152697, , 2020

248. S. Resveratrol Improves Alcoholic Fatty Liver Disease by Downregulating HIF-1α Expression and Mitochondrial ROS Production, Ma , Z.Zhang , Y.Li , Q.Xu , M.Bai , J.Wu, PLoS ONE12 , e0183426 . [ CrossRef ] [ PubMed, , 2017

249. Williams R. The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and-2, Qi JLang WGeisler JGWang PPetrounia IMai SSmith CAskari HStruble GT, J. Lipid Res . 53 : 1106-1116, , 2012

250. Y. Supplementation of Okra Seed Oil Ameliorates Ethanol-Induced Liver Injury and Modulates Gut Microbiota Dysbiosis in Mice, Zhang , J.Lu , Y.Yang , X.Zhao, Food Funct10 , 6385 ? 6398 . [ CrossRef ] [ PubMed, , 2019

251. Evaluation of Genotoxicity and 28-Day Oral Dose Toxicity on Freeze-Dried Powder of Tenebrio molitor Larvae ( Yellow Mealworm, Han , S.R .Yun , E.Y .Kim , J.Y .Hwang , J.S .Jeong , E.J .Moon , K.S, 30 , 121 ? 130 . [ CrossRef, , 2014

252. Therapeutic potency of fermented field water ? dropwort ( Oenanthe javanica ( Blume ) DC . ) in ethanol-induced liver injury, Lee DHLee JSLee IHHong JT, RSC Adv . 10 : 1544-1551, , 2020

253. Y.C . Protective Effects of Antioxidant Egg-Chalaza Hydrolysates Against Chronic Alcohol Consumption-Induced Liver Steatosis, 51 . Yang ,. ; Lin ,. ; Lin ,. ; Wang ,. ; Wu ,. ; Chou ,. ; FuS.G. ; Chen, Mice . J. Sci .2019 , 99 , 2300 ? 2310 ., , Agric

254. T. Pyroglutamic Acid Stimulates DNA Synthesis in Rat Primary Hepatocytes through the Mitogen-Activated Protein Kinase Pathway, Inoue , S.Okita , Y.de Toledo , A.Miyazaki , H.Hirano , E.Morinaga, Biosci . Biotechnol . Biochem79 , 795 ? 798 . [ CrossRef ] [ PubMed, , 2015

255. Yun , E.Y . Tenebrio molitor Larvae Inhibit Adipogenesis through AMPK and MAPKs Signaling in 3T3-L1 Adipocytes and Obesity in, Seo , M. ;, T.W . ;, M.Y .Baek , M. ;, J.S . ;, M.A ., Diet-Induced Obese Mice .Sci . 2017 , 18 , 518 . [, , Mol

256. Eder K. Insect meal as alternative protein source exerts pronounced lipid-lowering effects in hyperlipidemic obese Zucker rats, Gessner DKSchwarz AMeyer SWen GMost EZorn HRingseis R, J. Nutr . 149 : 566-577, , 2019

257. Gillevet P. Intestinal dysbiosis : a possible mechanism of alcohol ? induced endotoxemia and alcoholic steatohepatitis in rats, Mutlu EKeshavarzian AEngen PForsyth CBSikaroodi M, Alcohol Clin . Exp . Res33 : 1836-1846, , 2009

258. Hepatoprotective Effect of Bacillus subtilis-fermented silkworm ( Bombyx mori L. ) extract on an alcoholic fatty liver in rats, Kim THAhn HYKim YWSim SYSeo KICho YS, J . Life . Sci28 , 697 ? 707, , 2018

259. Li YR. Oxidative stress and redox signaling mechanisms of alcoholic liver disease : updated experimental and clinical evidence, Zhu HJia ZMisra H, J . Dig . Dis . 13 : 133-142, , 2012

260. Wu S. Resveratrol improves alcoholic fatty liver disease by downregulating HIF-1α expression and mitochondrial ROS production, Ma ZZhang YLi QXu MBai J, PLoS One12 : e0183426, , 2017

261. Liangpunsakul S. Trends in alcoholic hepatitis-related hospitalizations , financial burden , and mortality in the United States, Jinjuvadia R, J. Clin . Gastroenterol . 49 : 506- 511, , 2015

262. S. Dietary L-Leucine and L-Alanine Supplementation Have Similar Acute Effects in the Prevention of High-Fat Diet-Induced Obesity, Freudenberg , A.Petzke , K.J .Klaus, Amino Acids44 , 519 ? 528 . [ CrossRef ] [ PubMed, , 2013

263. Wang C. The regulation of alfalfa saponin extract on key genes involved in hepatic cholesterol metabolism in hyperlipidemic rats, Shi YGuo RWang XYuan DZhang SWang JYan X, PLoS One9 : e88282, , 2014

264. Zhao Y. Supplementation of okra seed oil ameliorates ethanol-induced liver injury and modulates gut microbiota dysbiosis in mice, Zhang JLu YYang X, Food Funct . 10 : 6385-6398, , 2019

265. , E.Y . Tenebrio molitor Larvae Inhibit Adipogenesis through AMPK and MAPKs Signaling in 3T3-L1 Adipocytes and Obesity in High-Fat, M.C . ; GooT.W . ; ChungM.Y . ; BaekM.H . ; HwangJ.S . ; KimM.A . ;, Obese Mice . Int . J.. 2017 , 18 , E518, , .

266. , J.S . ; Moon , K.S . Safety Assessment of Freeze-Dried Powdered Tenebrio Molitor Larvae ( Yellow Mealworm ) as Novel Food Source, S.R . ; LeeB.S . ; JungK.J . ; YuH.J . ; YunE.Y . ;, Evaluation of 90-Day Toxicity inRegul . Toxicol . Pharmacol . 2016 ,, , Rats

267. Cohen P. The TRAF-associated protein TANK facilitates cross-talk within the IκB kinase family during Toll-like receptor signaling, Clark KTakeuchi OAkira S, Proc . Natl . Acad . SciU.S.A. 108 : 17093-17098, , 2011

268. Investigating RNA expression profiles altered by nicotinamide mononucleotide therapy in a chronic model of alcoholic liver disease, Assiri MAAli HRMarentette JOYun YLiu JHirschey MDSaba LMHarris PSFritz KS, Hum . Genomics13 : 65, , 2019

269. Protective effects of antioxidant egg ? chalaza hydrolysates against chronic alcohol consumption ? induced liver steatosis in mice, Yang KTLin YLLin YXWang SYWu YHSChou CHFu SGChen YC, J. Sci . Food Agric . 99 : 2300-2310, , 2019

270. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, 172 . Bradford MM, Anal . Biochem72 : 248-254 . 1976,

271. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Bradford MM, Anal . Biochem1976 , 72 , 248 ? 254 . [ CrossRef,

272. Changes in the amino acid profiles and free radical scavenging activities of Tenebrio molitor larvae following enzymatic hydrolysis, Tang YDebnath TChoi EJKim YWRyu JPJang SChung SUChoi YJKim EK, PLoS One13 : e0196218, , 2018

273. Duchini A. Etiopathogenesis of nonalcoholic steatohepatitis : role of obesity , insulin resistance and mechanisms of hepatotoxicity, Guturu P, Int . J. Hepatol212865, , 20122012

274. ; Li , Z. Caspase 3-Mediated Cytotoxicity of Mealworm Larvae ( Tenebrio molitor ) Oil Extract against Human Hepatocellular Carcinoma, , R.A. ;, Q. ;, H. ;, H. ;, N. ;, K. ;, R. ;, L. ;,, Colorectal Adenocarcinoma. 2020 , 250 , 112438, , J.

275. Lee E. Alteration of gut microbiota composition by short ? term low-dose alcohol intake is restored by fermented rice liquor in mice, Lee JEHa JSPark HY, Food Res . Int . 128 : 108800, , 2020

276. Ahn G. In vivo hepatoprotective effects of a peptide fraction from krill protein hydrolysates against alcohol-induced oxidative damage, Park SYFernando IPSHan EJKim MJJung KKang DSAhn CB, Mar . Drugs 17 : 690, , 2019

277. Ethanol-induced liver injury and changes in sulfur amino acid metabolomics in glutathione peroxidase and catalase double knockout mice, Kim SJLee JWJung YSKwon DYPark HKRyu CSKim SKOh GTKim YC, J. Hepatol50 : 1184- 1191, , 2009

278. Hepatoprotective effects of steamed and freeze-dried mature silkworm larval powder against ethanol-induced fatty liver disease in rats, Lee DYHong KSSong MYYun SMJi SDSon JGKim EH, Foods 9 : 285, , 2020

279. Szabo G. The critical role of toll ? like receptor ( TLR ) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88, Hritz IMandrekar PVelayudham ACatalano DDolganiuc AKodys KKurt Jones E, Hepatology 48 : 1224- 1231, , 2008

280. X. Optimal Management for Alcoholic Liver Disease : Conventional Medications , Natural Therapy or Combination ? World J. Gastroenterol, Kim , M.S .Ong , M.Qu, 22 , 8 ? 23 . [ CrossRef, , 2016

281. Morinaga T. Pyroglutamic acid stimulates DNA synthesis in rat primary hepatocytes through the mitogen ? activated protein kinase pathway, Inoue SOkita Yde Toledo AMiyazaki HHirano E, Biosci . Biotechnol . Biochem79 : 795-798, , 2015

282. Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase, Marklund S, Eur . J. Biochem47 : 469-474, , 1974

283. cardio-and neuro ? protective effects of Tenebrio molitor ( Coleoptera : Tenebrionidae ) defatted larvae in spontaneously hypertensive rats, Pessina FFrosini MMarcolongo PFusi FSaponara SGamberucci AValoti MGiustarini DFiorenzani PGorelli B. Antihypertensive, PLoS One15 : e0233788, , 2020

284. 11. Tajiri, K.; Shimizu, Y. Branched-Chain Amino Acids in Liver Diseases. World J. Gastroenterol. 2013, 19, 7620–7629. [CrossRef] [PubMed], Tajiri , K.Shimizu , Y. Branched-Chain Amino, 19 , 7620 ? 7629CrossRef ] [ PubMed, , 2013

285. Ahn H. Effect of Tenebrio molitor larvae fermented with Saccharomyces cerevisiae M1 ( KACC 93023 ) on non-alcoholic fatty liver-induced rats, Sim SJang SCho Y, J . Life Sci30 : 434-442, , 2020

286. Defatted Tenebrio molitor larva fermentation extract modifies steatosis , inflammation and intestinal microflora in chronic alcohol-fed rats, Choi RYHam JRRyu HSLee SSMiguel MAPaik MJJi MPark KWKang KYLee HI, Nutrients 12 : 1426, , 2020

287. Mapping of the circulating metabolome reveals α-ketoglutarate as a predictor of morbid obesity-associated non-alcoholic fatty liver disease, guez-Gallego EGuirro MRiera-Borrull MHernandez-Aguilera ACasado RFernandez-Arroyo SBeltran-Debon RSabench FHernandez MDel Castillo D, Int . J. Obes . 39 : 279-287, , 2015

288. antioxidant activity , and inhibitory effect on pancreatic lipase of extracts from the edible insects Acheta domesticus and Tenebrio molitor, 156. del Hierro JNrrez-Docio AOtero PReglero GMartin D. Characterization, Food Chem . 309 : 125742, , 2020

289. ; Kang , J.X . Suppression of Acute Ethanol-Induced Hepatic Steatosis by Docosahexaenoic Acid is Associated with Downregulation of Stearoyl-CoA, Huang , L.L; Wan ,; Wang , B.He , C.W; Ma , H.Li , T.W, 1 and Inflammatory Cytokines . Prostaglandins Leukot. Fatty Acids 2013 , 88 , 347 ? 353 ., , .

290. The edible insect Gryllus bimaculatus protects against gut-derived inflammatory responses and liver damage in mice after acute alcohol exposure, Hwang BBChang MHLee JHHeo WKim JKPan JHKim YJKim JH, Nutrients11 , 857 . [ CrossRef, , 2019

291. , C.B . Hepatoprotective Effect of Peptic Hydrolysate from Salmon Pectoral Fin Protein Byproducts on Ethanol-Induced Oxidative Stress in Sprague, J.Y . ; ChaJ.Y . ; ChoY.S . ; AhnH.Y . ; LeeJ.H . ; ChoY.S . ;, Dawley Rats . Food. 2013 , 51 , 648 ? 653, , .

292. Metabolomics study of serum from a chronic alcohol-fed rat model following administration of defatted Tenebrio molitor larva fermentation extract, 187 . Choi RYJi MLee MKPaik MJ, Metabolites 10 : 436, , 2020

293. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment, 261 . Bull-Otterson LFeng WKirpich IWang YQin XLiu YGobejishvili LBarve SAyvaz TPetrosino J, PLoS One8 : e53028, , 2013

294. Yoshimatsu H. TNF-α induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein ? 1c ( SREBP-1c ), Endo MMasaki TSeike M, Exp . Biol . Med232 : 614-621, , 2007

295. Tenebrio molitor larvae inhibit adipogenesis through AMPK and MAPKs signaling in 3T3- L1 adipocytes and obesity in high-fat diet-induced obese mice, Seo MGoo TWChung MYBaek MHwang JSKim MYun EY, Int . J. Mol . Sci18 : 518, , 2017

296. Intraventricular administration of Tenebrio molitor larvae extract regulates food intake and body weight in mice with high-fat diet ? induced obesity, Seo MKim JMoon SSHwang JSKim MA, Nutr . Res . 44 : 18-26, , 2017

297. Probiotics ( Lactobacillus rhamnosus R0011 and acidophilus R0052 ) reduce the expression of toll-like receptor 4 in mice with alcoholic liver disease, Hong MKim SWHan SHKim DJSuk KTKim YSKim MJKim MYBaik SKHam YL, PLoS One10 : e0117451, , 2015

298. Wang Y. Lactobacillus rhamnosus granules dose-dependently balance intestinal microbiome disorders and ameliorate chronic alcohol-induced liver injury, Gu ZWu YWang YSun HYou YPiao CLiu J, J. MedFood 23 : 114-124, , 2020

299. Hepatoprotective effect of peptic hydrolysate from salmon pectoral fin protein byproducts on ethanol-induced oxidative stress in Sprague ? Dawley rats, 241 . Je JYCha JYCho YSAhn HYLee JHCho YSAhn CB, Food Res . Int . 51 : 648- 653, , 2013

300. , et al . Effects of branched-chain amino acids ( BCAAs ) on the progression of advanced liver disease : a Korean nationwide , multicenterretrospective ,, . Park, Tak, Park, Kweon, Jang, Lee, Bae, Jang, Kim, , cohort study . Medicine ( Baltimore, , 96

301. Metabolomic Analysis using LC-TOF/MS and LC-MS/MS for Revealing Metabolic Alterations Linked to Alcohol-Induced Hepatic Steatosis in Rat Serum and Plasma, Wu , H.Feng , F. Untargeted, RSC Adv6 , 28279 ? 28288 . [ CrossRef, , 2016

302. Stahl A. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia, Doege HGrimm DFalcon ATsang BStorm TAXu HOrtegon AMKazantzis MKay MA, J. Biol . Chem . 283 : 22186-22192, , 2008

303. Gasbarrini G. Energy expenditure , substrate oxidation , and body composition in subjects with chronic alcoholism : new findings from metabolic assessment, Addolorato GCapristo EGreco AVStefanini GF, Alcohol Clin . Exp . Res21 : 962-967, , 1997

304. You M. Regulation of hepatic lipin ? 1 by ethanol : role of AMP ? activated protein kinase/sterol regulatory element ? binding protein 1 signaling in mice, Hu MWang FLi XRogers CQLiang XFinck BNMitra MSZhang RMitchell DA, Hepatology 55 : 437-446, , 2012

305. Combined metadoxine and garlic oil treatment efficaciously abrogates alcoholic steatosis and CYP2E1 induction in rat liver with restoration of AMPK activity, 210 . Ki SHChoi JHKim CWKim SG, Chem . Biol . Interact169 : 80-90, , 2007

306. Li Z. Caspase 3-mediated cytotoxicity of mealworm larvae ( Tenebrio molitor ) oil extract against human hepatocellular carcinoma and colorectal adenocarcinoma, Wu RADing QLu HTan HSun NWang KHe RLuo LMa H, J. Ethnopharmacol . 250 : 112438, , 2020

307. Lu S. The effect of alcohol and hydrogen peroxide on liver hepcidin gene expression in mice lacking antioxidant enzymes , glutathione peroxidase-1 or catalase, Harrison-Findik DD, Biomolecules 5 : 793-807, , 2015

308. M. Antioxidant and Anti-Inflammatory Activities of Hydrolysates and Peptide Fractions Obtained by Enzymatic Hydrolysis of Selected Heat-Treated Edible Insects, Zieli ´nskaE.Baraniak , B.Kara´s, Nutrients9 , E970 . [ CrossRef ] [ PubMed, , 2017

309. Kim S. Chronic alcohol exposure stimulates adipose tissue lipolysis in mice : role of reverse triglyceride transport in the pathogenesis of alcoholic steatosis, Zhong WZhao YTang YWei XShi XSun WSun XYin XSun X, Am . J. Pathol180 : 998-1007, , 2012

310. Omega-3 polyunsaturated fatty acids ameliorate ethanol-induced adipose hyperlipolysis : a mechanism for hepatoprotective effect against alcoholic liver disease, Wang MZhang XMa LFeng RYan CSu HHe CKang JXLiu BWan JB, Biochim . BiophysActa . Mol . Basis . Dis . 1863 : 3190-3201, , 2017

311. D. Characterization , Antioxidant Activity , and Inhibitory Effect on Pancreatic Lipase of Extracts from the Edible Insects Acheta domesticus and Tenebrio molitor, 5. del Hierro , J.N .rrez-Docio , A.Otero , P.Reglero , G.Martin, Food Chem309 , 125742 . [ CrossRef, , 2020

312. Safety assessment of freeze-dried powdered Tenebrio molitor larvae ( yellow mealworm ) as novel food source : evaluation of 90-day toxicity in Sprague-Dawley rats, Han SRLee BSJung KJYu HJYun EYHwang JSMoon KS, Regul . Toxicol . Pharmacol . 77 : 206-212, , 2016

313. Salminen S. Intestinal integrity and Akkermansia muciniphila , a mucin-degrading member of the intestinal microbiota present in infants , adults , and the elderly, Collado MCDerrien MIsolauri Ede Vos WM, Appl . Environ . Microbiol73 : 7767-7770, , 2007

314. Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice, Lu YWu DWang XWard SCCederbaum AI, Free Radic . Biol . Med49 : 1406-1416, , 2010

315. Suppression of acute ethanol-induced hepatic steatosis by docosahexaenoic acid is associated with downregulation of stearoyl-CoA desaturase 1 and inflammatory cytokines, Huang LWan JWang BHe CMa HLi TKang JX, Prostaglandins . Leukot . Essent . Fatty Acids 88 : 347-353, , 2013

316. Practice Guideline Committee of the American Association for the Study of Liver Diseases and the Practice Parameters Committee of the American College of Gastroenterology, O'shea RSDasarathy SMcCullough AJ, Alcoholic liver diseaseHepatology 51 : 307-328, , 2010

317. Eder K. The antisteatotic and hypolipidemic effect of insect meal in obese Zucker rats is accompanied by profound changes in hepatic phospholipid and 1 ? carbon metabolism, 161 . Meyer SGessner DKWen GMost ELiebisch GZorn HRingseis R, Mol . Nutr . Food Res63 : e1801305, , 2019

318. Lakshman MR. Low-ω3 fatty acid and soy protein attenuate alcohol-induced fatty liver and injury by regulating the opposing lipid oxidation and lipogenic signaling pathways, Reyes-Gordillo KShah RVaratharajalu RGarige MLeckey LC, Oxid . Med . Cell Longev1840513, , 20162016

319. Feng F. Untargeted metabolomic analysis using LC-TOF/MS and LC ? MS/MS for revealing metabolic alterations linked to alcohol-induced hepatic steatosis in rat serum and plasma, Wu H, RSC Adv6 : 28279-28288, , 2016

320. Miura , C. ; Miura , T. Replacement of Fish Meal by Defatted Yellow Mealworm ( Tenebrio molitor ) Larvae in Diet Improves Growth Performance and Disease Resistance in Red Seabream, 14 . IdoA. ; HashizumeA. ; OhtaT. ; TakahashiT., major ) . Animals 2019 , 9 , E100 . [[ PubMed ] Nutrients 2020 ,, , (CrossRef

321. D. Metabolomics Study of the Hepatoprotective Effect of Phellinus igniarius in Chronic Ethanol-Induced Liver Injury Mice using UPLC-Q/TOF-MS Combined with Ingenuity Pathway Analysis, Dong , Y.Qiu , P.Zhao , L.Zhang , P.Huang , X.Li , C.Chai , K.Shou, Phytomedicine74 , 152697 . [ CrossRef, , 2018

322. Miura T. Replacement of fish meal by defatted yellow mealworm ( Tenebrio molitor ) larvae in diet improves growth performance and disease resistance in red seabream ( Pargus major ), Ido AHashizume AOhta TTakahashi TMiura C, Animals 9 : E100, , 2019

323. Chronic alcohol consumption disrupted cholesterol homeostasis in rats : down ? regulation of low ? density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver, Wang ZYao TSong Z, Alcohol . Clin . Exp . Res34 : 471-478, , 2010

324. Chronic oral administration of Tenebrio molitor extract exhibits inhibitory effect on glucocorticoid receptor overexpression in the hippocampus of ovariectomy ? induced estrogen deficient Mice, Kim GHBaek HKLee JSKim SJYi SS, J . Food Sci84 , 687 ? 694 . [ CrossRef ] [ PubMed, , 2019

325. Chronic ethanol and triglyceride turnover in white adipose tissue in rats inhibition of the anti-lipolytic action of insulin after chronic ethanol contributes to increased triglyceride degradation, Kang LChen XSebastian BMPratt BTBederman IRAlexander JCPrevis SFNagy LE, J. Biol . Chem282 : 28465-28473, , 2007

326. Increased Hepatocellular Uptake of Long Chain Fatty Acids Occurs by Different Mechanisms in Fatty Livers Due to Obesity or Excess Ethanol Use , Contributing to Development of Steatohepatitis in Both Settings, Berk , P.D .Zhou , S.Bradbury , M.W, 116 , 335 ? 344 . [ PubMed, , 2005