부추 추출물의 PCSK9 억제를 통한 LDL 콜레스테롤 저감 효능

최효경(Hyo-Kyoung Choi),김효진(Hyo Jin Kim),황진택(Jin-Taek Hwang),정민유(Min-Yu Chung) 한국식품영양과학회 2017 한국식품영양과학회지 Vol.46 No.11

본 연구에서는 부추 추출물(Allium tuberosum, AT) 보충식이(1%, w/w)를 12주간 고지방 식이와 함께 마우스에 제공하였다. Western diet(WD)군의 마우스는 low fat diet (LD)군의 마우스보다 유의적으로 높은 총 콜레스테롤 및 LDL 콜레스테롤 수치를 보였으며, 이는 AT 보충식이에 의하여 유의적으로 감소하였다. 또한, 마우스 간 조직 내 PCSK9 유전자가 AT에 의해 유의적으로 감소하였다. 이를 통해 AT의 PCSK9 억제를 통한 LDL 콜레스테롤 저감 가능성을 확인하였다. HepG2 세포주를 지방 부족 환경으로 만들고 AT를 처리하여 PCSK9과 LDLR, 그리고 관련 단백질 및 유전자의 조절 정도를 평가하였다. 그 결과 독성 없는 농도의 AT는 LDLR 단백질 발현을 농도 의존적으로 증가시켰으며, 특히 400 μg/mL의 AT는 PCSK9 단백질 발현을 억제하였다. 유사하게 AT는 LDLR 유전자 발현량을 유의적으로 증가시켰고, PCSK9의 발현량은 유의적으로 감소시켰다. PCSK9의 억제는 SREBP2가 아닌 AT에 의해 유의적으로 감소한 HNF1α 전사인자 때문이다. AT에 의한 LDLR 유전자의 SREBP2-independent 한 조절은 추후 연구가 필요하다. 다음으로 PCSK9 억제제인 AT의 LDLR 단백질 degradation 및 단백질 합성 조절을 평가하기 위해 지방 제거 상태의 HepG2 세포에 lysosomal degradation inhibitor인 BA1과 단백질 합성 억제제인 CHX를 처리하여 LDLR 단백질 발현 변화를 관찰하였다. AT(400 μg/mL)는 LDLR 단백질의 합성 억제를 block 하였고, 이는 LDLR의 lysosomal degradation을 막음으로써 이루어짐을 알 수 있었다. PCSK9 억제는 고콜레스테롤 혈증이나 콜레스테롤 저항성치료 혹은 예방 소재 개발에서 중요한 타깃이 될 수 있으며, 부추와 같은 PCSK9 억제 활성을 지닌 천연물 혹은 식품 소재의 발굴이 기존의 치료와 병행하여 또는 독립적으로도 쓰일 수 있는 안전한 소재로써 제안될 수 있다. 추후 동물 실험에서 부추 추출물 및 활성 성분의 PCSK9 활성 억제 연구 및 나아가 부추의 PCSK9 억제를 통한 콜레스테롤 저감 효능 임상 연구 등이 제안될 수 있겠다. Accumulation of excess low density lipoprotein (LDL) cholesterol in the blood can initiate and accelerate atherosclerosis. Statins mediate the transactivation of proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn limits their cholesterol-lowering effects via LDL receptor (LDLR) degradation. The objective of this study was to investigate whether or not Allium tuberosum (AT) regulates LDLR and PCSK9. Mice were fed a low fat control diet (LD) or Western diet (WD) supplemented with AT (1%, w/w). AT significantly attenuated total and LDL cholesterol levels in mice fed WD (P<0.05). AT also significantly inhibited hepatic PCSK9 gene expression (P<0.05) while AT maintained hepatic LDLR gene expression. To further investigate AT-mediated PCSK9 regulation, HepG2 cells were treated with 10% delipidated serum (DLPS) in the presence or absence of AT. Non-toxic level of AT dose-dependently increased the LDLR protein level, and AT at 400 μg/mL markedly inhibited PCSK9 protein expression. Similarly, AT significantly increased LDLR gene expression, whereas it significantly down-regulated PCSK9 gene expression. AT-mediated reduction of PCSK9 gene expression is likely due to decreased hepatic nuclear factor 1α (HNF1α) expression, but not SREBP2 in HepG2 cells under lipid-depleted conditions. AT-mediated PCSK9 inhibition contributed to LDLR protein stabilization via protection against LDLR lysosomal degradation in HepG2 cells under lipid-depleted conditions. Further investigation is warranted to determine the active components of AT and whether or not these components are effective in reducing hypercholesterolemia.

PCSK9 저해제와 인지 기능 관련 이상사례: 세계보건복지기구 데이터베이스 VigiBase를 활용한 약물감시 연구

박다현,배성호,배지환,이혜성,최영준,신주영 한국에프디시규제과학회 2023 FDC법제연구 Vol.18 No.2

전구단백질 전환효소 서브틸리신/켁신 9형 (PCSK9) 저해제는 심혈관 질환 환자에게 사용되는 새로운 지질 강 하제이다. 임상시험에서 PCSK9 저해제의 인지 기능 장애에 대한 안전성이 검증되었지만 신경인지 기능 장애 사례가 보고되며 실사용 환경에서의 근거가 증가하고 있다. 이는 PCSK9 저해제가 인지 기능 장애의 위험을 증가시킬 수 있 음을 시사한다. 이에 따라, 본 연구는 PCSK9 저해제와 인지 기능 계통의 이상사례 간 연관성을 확인하는 것을 목표 로 한다. 1968년 1월부터 2022년 12월까지의 세계보건기구 VigiBase 데이터를 사용하여 관찰적 약물 감시 연구를 수 행하였다. PCSK9 저해제인 알리로쿠맙과 에볼로쿠맙의 개별 이상사례 보고서(ICSR)를 연구약물로 하여 다른 모든 약 물의 보고오즈비를 비교했다. 1차 평가 지표로 인지 기능 이상 관련 부작용은 규제 활동을 위한 의학 사전 (MedDRA) 시스템의 상위 단계군 용어 중 ‘인지 및 주의 장애’와 ‘정신적 장애’를 사용하여 정의하였으며, 2차 평가 지표로 세부 인지 기능 관련 이상사례를 나타내었다. PCSK9 저해제에 대한 114,293개의 보고서(258,099개의 약물-이상사례 쌍) 중 2094개(7,988개의 약물-이상사례 쌍)가 인지 기능 이상 부작용에 대한 건으로 확인되었다. ICSR 중 54%는 여성 환자 를 포함했으며, 41%는 65세, 대다수 (82%)는 에볼로쿠맙을 투여받았다. PCSK9 저해제와 인지 기능 이상 관련 부 작용에 대해 뷸균형 정보가 관측되었다(ROR 1.70, 95% CI 1.63-1.77). 세부적으로 인지 장애(ROR 1.47, 95% CI 1.28- 1.69), 기억 이상(ROR 2.72, 95% CI 2.56-2.88), 기억 상실증(ROR 1.50, 95% CI 1.36-1.65)가 유의한 실마리 정보로 탐지되었다. 본 약물감시 연구를 통해 PCSK9 저해제의 사용과 관련된 인지 기능 이상에 대한 보고가 증가한 것을 확 인할 수 있었으며, 특히 PCSK9 저해제를 투여받는 고령층 환자 사용에 있어 ‘기억 이상’ 부작용에 대해 주의 깊게 고 려해야 한다. 결과는 PCSK9 저해제 사용자의 인지 기능 이상에 대한 체계적 감시의 필요성을 시사한다. Protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel lipid-lowering agents used in patients with cardiovascular diseases. Despite reassuring safety data from pivotal trials, increasing evidence from realworld studies suggests that PCSK9 inhibitors may increase the risk for cognitive dysfunction. This study aimed to identify signals of cognitive dysfunction-related adverse events (AEs) associated with PCSK9 inhibitors. We performed an observational pharmacovigilance study using the World Health Organization (WHO) VigiBase data up to December 2022. We included individual case safety reports (ICSRs) of the PCSK9 inhibitors alirocumab and evolocumab and compared them with those of other drugs. As the primary outcome, cognitive dysfunction was defined using the Medical Dictionary for Regulatory Activities (MedDRA) system’s High Level Group Term (HLGT) ‘Cognitive and attention disorders and disturbances’ and ‘Mental impairment disorders’ The secondary outcomes indicated specific classifications of cognitive dysfunction-related AEs. Among 114,293 reports (258,099 drug-AE pairs) on PCSK9 inhibitors, 8464 (31,951 drug-AE pairs) were identified as cognitive dysfunction-related AEs. Among the ICSRs, 54% included female patients, 41% persons aged 65 years, and the majority (82%) were for those who received evolocumab. The study revealed a significant disproportionality for cognitive dysfunction with PCSK9 inhibitors(ROR 1.70, 95% CI 1.63-1.77). Specifically, significant signals were identified for cognitive disorder (ROR 1.47, 95% CI 1.28-1.69), memory impairment (ROR 2.72, 95% CI 2.56-2.88), and amnesia(ROR 1.50, 95% CI 1.36-1.65). This pharmacovigilance study identified an increased reporting of cognitive dysfunction associated with the use of PCSK9 inhibitors, particularly emphasizing caution regarding ‘memory abnormalities’ in elderly patients receiving PCSK9 inhibitors. Our findings support the need for the systematic surveillance of cognitive dysfunctions among PCSK9 inhibitor users.

PCSK9과 LDL-C: 운동의 역할

진재호,조우연,노지헌,이상기 한국운동생리학회 2020 운동과학 Vol.29 No.4

PURPOSE: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a pivotal regulator of low lipoprotein-cholesterol (LDL-C) and LDL receptor (LDLR) metabolism, and the interest in PCSK9 has increased in cardiovascular diseases. Exercise reduces blood LDL-C via PCSK9-LDLR pathway in the liver and the vasculature. However, the mechanism of exercise-induced inhibition of PCSK is unclear. The aim of this review is to describe the role of exercise on PCSK9-LDLR axis in cardiovascular diseases. METHODS: This study review 34 previous studies focusing on the effect of exercise on PCSK9 in the human and animal. RESULTS: The effects of exercise and lifestyle intervention on hepatic and circulating PCSK9 are controversial. However, exercise consistently increases hepatic LDLR, and inhibits atherosclerosis via suppression of PCSK9 and LOX-1 in atherosclerotic region. CONCLUSIONS: Even though experimental data are still very limited, exercise training can improves blood LDL-C via inhibition of PCSK9 and enhancement of LDLR in liver and vasculature. The study of exercise on PCSK9 are urgently needed.

HepG2 세포에서 Isoeugenol의 PCSK9 억제 효능

최효경(Hyo-Kyoung Choi),정민유(Min-Yu Chung) 한국식품영양과학회 2020 한국식품영양과학회지 Vol.49 No.9

본 논문에서는 isoeugenol의 PCSK9 억제능 관련 메커니즘을 규명하였다. HepG2 세포를 지방 부족 환경으로 만들고 isoeugenol을 처리하여 PCSK9과 LDLR, 그리고 전사인자의 단백질 및 유전자 발현 조절을 측정하였다. 독성 없는 농도의 isoeugenol(~100 μM)은 LDLR의 단백질 발현 조절에 관여하지 않았지만, PCSK9의 단백질 및 유전자 발현을 감소시켰다. Isoeugenol은 PCSK9 조절에 독립적으로 관여하는 전사인자인 HNF1α의 유전자 및 단백질 조절에는 관여하지 않았다. 따라서 isoeugenol은 SREBP2를 통해 PCSK9과 LDLR의 유전자 발현을 억제하였음을 알 수 있었다. 또한 DLPS로 지방 고갈이 유도된 HepG2 세포에 스타틴(rosuvastatin 0.2 μM)과 isoeugenol을 동시 처리했을 때, isoeugenol은 스타틴에 의해 증가한 PCSK9의 발현을 농도의존적으로 감소시켰다. 고콜레스테롤혈증 동물 모델에서도 isoeugenol의 이러한 PCSK9 억제 효능이 관찰되는지에 대한 추후 연구가 필요하다. 본 연구를 통하여 isoeugenol 은 PCSK9 억제 활성을 나타내며 스타틴 치료와 병행하여 그 한계점을 보완할 수 있는 소재로서 제안될 수 있다. Hypercholesterolemia is a major cause of a number of different chronic diseases, including atherosclerosis. Statins for the treatment of hypercholesterolemia induce transactivation of low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 interferes with LDL cholesterol and its receptor binding, promoting LDLR degradation and thereby increasing circulating LDL cholesterol. In the current study, HepG2 cells were treated with 10% delipidated serum (DLPS) in the presence or absence of isoeugenol. Lipid depletion increased both LDLR and PCSK9 protein expression levels in HepG2 cells, and isoeugenol inhibited PCSK9 in HepG2 cells. The objective of this study was to investigate the mechanism by which isoeugenol inhibits PCSK9 and subsequently increases LDLR protein expression HepG2 cells under lipid depletion conditions. A non-toxic level of isoeugenol reduced PCSK9 protein expression without affecting LDLR protein expression. Lipid depletion enhanced gene expression of LDLR, PCSK9, and their transcription factors SREBP2 and HNF1α in HepG2 cells. Isoeugenol significantly attenuated LDLR, PCSK9, and SREBP2 gene expression (P<0.0001), but not HNF1α. Consistently, isoeugenol also markedly reduced SREBP2 protein expression, but not HNF1α. This suggests that isoeugenol-mediated SREBP2 downregulation reduced LDLR and PCSK9 gene expression, and attenuated PCSK9 expression contributed to maintenance of LDLR protein expression in HepG2 cells under lipid depletion conditions. In DLPS-treated HepG2 cells, isoeugenol dose-dependently reduced statin-mediated elevation of PCSK9 protein expression. This study suggests isoeugenol as a potential statin co-treatment material and PCSK9 inhibitor.

콜레스테롤 식이가 Pcsk9 유전자 조절을 통해 남성 생식기관에 미치는 영향

임화선,배효철,송권화 한국식품위생안전성학회 2016 한국식품위생안전성학회지 Vol.31 No.2

Proprotein convertase subtilisin/kexin type 9 (PCSK9), is a protein mainly secreted by a liver. The PCSK9 plays an important role in low density lipoprotein (LDL) metabolism acting as a repressor of LDL receptor through transportation of the LDLR to the lysosome for degradation. Thus, the PCSK9 inhibitor suppresses PCSK9-regulated degradation of the LDL receptor as a LDL-lowering medicine. However, little is known about the role of PCSK9 in the reproductive system. Therefore, in the present study, we investigated Pcsk9 expression in male reproductive tracts including penises, prostates and testes using rats in response to their diets between a normal diet and a high-fat diet with cholesterol. Based on our previous study, the high-fat diet elevates concentration of total cholesterol and LDL in serum whereas it reduces the concentration of plasma high density lipoprotein (HDL). In addition, it dramatically affects to morphological changes of the male reproductive organs. Consistent with these results, the expression of Pcsk9 was substantially decreased in the penile tissues (P < 0.001) from rats fed a high fat diet as compared to a normal diet. Moreover, it slightly reduced in the prostate and testes (P < 0.05) of rats in response to a high fat diet. Localization of Pcsk9 was predominantly detected in urethral epithelium of penises, cylinder-shaped cells of prostate glands, and spermatogonia, spermatocytes and spermatid of testes of rats. Collectively, results of current study provide invaluable insights into the Pcsk9 gene with respect to its tissue- and cell-specific expression by a high fat diet with cholesterol.

PCSK9과 LDL-C: 운동의 역할

진재호 ( Jaeho Jin ),조우연 ( Wooyeon Jo ),노지헌 ( Ji Heon Noh ),이상기 ( Sang Ki Lee ) 대한운동사협회 2022 대한운동사협회 운동사대회자료집 Vol.2022 No.-

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a pivotal regulator of low lipoprotein-cholesterol (LDL-C) metabolism, and the interest in PCSK9 has increased in cardiovascular diseases. PURPOSE: Exercise reduces blood LDL-C via PCSK9-LDLR pathway in liver. However, the mechanism of exercise-induced inhibition of PCSK is not unclear. The aim of this review is to describe the role of exercise on PCSK9-LDLR axis in cardiovascular diseases. METHODS: This study reviews 34 previous studies focusing on the effect on exercise on PCSK9 in the human and animal. RESULTS: The effects of exercise and lifestyle intervention on hepatic and circulating PCSK9 are controversial. However, exercise consistently increases hepatic LDLR, and inhibits atherosclerosis via suppression of PCSK9 and LOX-1 in atherosclerotic region. CONCLUSIONS: Even though experimental data are still very limited, exercise training can improves blood LDL-C via inhibition of PCSK9 and enhancement of LDLR in liver and vasculature. The study of exercise on PCSK9 are urgently needed.

In silico Screening of Chemical Libraries to Develop Inhibitors That Hamper the Interaction of PCSK9 with the LDL Receptor

민동국,박상욱,이현숙,이나래,이찬주,송현주,양가을,윤도준 연세대학교의과대학 2015 Yonsei medical journal Vol.56 No.5

Purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulationof the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR. Materials and Methods: We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silicoscreening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo. Results: A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependentmanner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice. Conclusion: Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.

PCSK9 regulates myocardial ischemia–reperfusion injury through parkin/pink1-mediated autophagy pathway

Huang Guangwei,Bao Hailong,Zhan Peng,Lu Xiyang,Duan Zonggang,Xiong Xinlin,Lin Muzhi,Wang Bing,An Hongxin,Xiahou Luanda,Zhou Haiyan,Luo Zhenhua,Li Wei 대한독성 유전단백체 학회 2024 Molecular & cellular toxicology Vol.20 No.2

Objectives This study aimed at investigating the role of the proprotein convertase subtilisin/Kexin type 9 (PCSK9)-mediated autophagy on myocardial ischemia/reperfusion injury (MIRI). To determine the relationship between autophagy, apoptosis, fibrosis, and inflammation in the myocardium, to provide experience in preventing and treating the myocardial ischemia/reperfusion (I/R) injury. Methods An AC16 hypoxia-reoxygenation model and a rat myocardial ischemia–reperfusion model were established. The concentrations of cardiac troponin T (cTnT) and creatine kinase-MB (CKMB) in plasma were measured by ELISA. To determine the size of the myocardial infarction, TTC/EB staining was performed. In addition to identifying pathological changes in myocardial tissue, Masson’s trichrome stains and H&E stains were used to identify pathological changes. Echocardiography was employed to detect cardiac function. Western blot analysis was then performed to detect the protein expression of Parkin, Pink1, and markers associated with autophagy (Beclin-1, p62, LC3). Results A significant increase in PCSK9 was observed in the myocardium during H/R. In the cardiac-specific PCSK9 knockdown model, cardiac autophagy was significantly inhibited, whereas cardiac-specific PCSK9 overexpression promoted cardiac autophagy. In vivo studies have demonstrated a significant decrease in cardiac autophagy when the PCSK9 inhibitor was administered. Apoptosis induced by I/R was greatly decreased, and myocardial infarction size and function were both improved by PCSK9 inhibitors. Mechanistically, the PCSK9 inhibitor improved the degree of myocardial fibrosis and inhibited the development of inflammation. Conclusions Our results demonstrated that increased PCSK9 via the parkin/pink1 signaling pathway contributes to I/R and H/R by exaggerating excessive autophagy during reperfusion/reoxygenation. In addition, the PCSK9 inhibitor blocked the development of inflammation and improved Infarct size, myocardial function, and myocardial fibrosis.

Black Raspberry Extract Enhances LDL Uptake in HepG2 Cells by Suppressing PCSK9 Expression to Upregulate LDLR Expression

송광훈,김영화,임아랑,김윤희 한국식품영양과학회 2018 Journal of medicinal food Vol.21 No.6

Black raspberry extract (BRE) has been widely used for treating prostate and urinary diseases and hyperlipidemia in Asia due to its significant lipid-lowering effects. The aim of this investigation was to evaluate the antihypercholesterolemia activity of BRE and the potential molecular mechanisms responsible for its antihypercholesterolemia activity by regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in the human liver cell line HepG2. Reporter-based functional assay was used to identify herbal extracts that suppress PCSK9 expression in the HepG2 cells. Quantitative real-time polymerase chain reaction, Western blot analysis, and immunofluorescence staining were used to evaluate whether BRE modulates low-density lipoprotein receptor (LDLR) expression by repressing the hepatic expression of PCSK9. The LDLR activity of the HepG2 cells was determined using an LDL uptake assay. Our finding revealed that BRE modulates LDLR expression by suppressing the hepatic expression of PCSK9. We found that the combination of simvastatin and BRE caused the synergic induction of LDLR expression and LDL-C uptake, whereas simvastatin alone increased the expression of PCSK9 in the HepG2 cells. These results clearly demonstrated that the BRE from black raspberry suppressed simvastatin-induced PCSK9 expression and improved LDL-C uptake by hepatocytes through the induction of LDLR expression. These results suggest that the suppression of PCSK9 expression by BRE may potentiate the hypolipidemic effect of statins.

Lignans from the fruits of <i>Schisandra chinensis</i> (Turcz.) Baill inhibit proprotein convertase subtilisin/kexin type 9 expression

Pel, Pisey,Chae, Hee-Sung,Nhoek, Piseth,Yeo, Woojin,Kim, Young-Mi,Chin, Young-Won Elsevier 2017 Phytochemistry Vol.136 No.-

<P><B>Abstract</B></P> <P>Bioactivity-guided fractionation of the fruits of <I>Schisandra chinensis</I>, using the proprotein convertase subtilisin-kexin type 9 (PCSK9) mRNA expression screening assay, led to isolation of two previously unknown lignans, 14-tigloylschinlignan D and <I>rel-</I>(7<I>R,</I> 8<I>R</I>, 7′<I>R</I>, 8′<I>R</I>)-manglisin E, along with 28 known compounds. All structures were established by NMR spectroscopic data as well as CD and MS analysis. All isolates were tested for their inhibitory activities on the mRNA expression of PCSK9. Of the tested compounds, four of the compounds <I>rel-</I>(7<I>R</I>, 8<I>R</I>, 7′<I>R</I>, 8′<I>R</I>)-manglisin E, (−)<B>-</B>schisandrin C, schinlignan D, and (+)-schisandrol B potently inhibited PCSK9 mRNA expression with IC<SUB>50</SUB> values of 3.15, 3.85, 0.36, and 1.10 μM, respectively. Furthermore, schinlignan D and (+)-schisandrol B were found to suppress PCSK9 protein expressions and schinlignan D deemed to increase low density lipoprotein receptor expression.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Fruits of <I>Schisandra chinensis</I> inhibited PCSK9 mRNA expression. </LI> <LI> 14-tigloylschinlignan D and <I>rel-</I>(7<I>R,</I> 8<I>R</I>, 7′<I>R</I>, 8′<I>R</I>)-manglisin E were identified. </LI> <LI> Four lignans potently inhibited PCSK9 mRNA expression. </LI> <LI> Schinlignan D suppressed PCSK9 protein and increased LDLR expression. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>Two lignans along with 28 known compounds were isolated and four lignans potently inhibited PCSK9 mRNA expression.</P> <P>[DISPLAY OMISSION]</P>