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Regulation of SIRT1 by MicroRNAs
최성이,Jongsook Kim Kemper 한국분자세포생물학회 2013 Molecules and cells Vol.36 No.5
Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that connects cellular energy levels to homeostatic responses by deacetylating and modulating the activities of many transcriptional regulators. Discovered as a longevity pro-tein in yeast, the mammalian SIRT1 has been intensively studied because of its great potential as a therapeutic target to benefit human health by preventing and improving many age-related diseases. There has been, therefore, substantial interest in developing agents that upregulate SIRT1 expression and activity. SIRT1 is regulated at multiple levels, including post-transcriptionally by microRNAs (miRs), powerful reg-ulators of diverse biological pathways. Here we discuss how expression and activity of SIRT1 and other sirtuins are inhibited by miRs and further discuss the therapeutic potential of targeting miRs for age-related diseases that involve SIRT1 dysfunction, focusing on obesity-related diseases.
MicroRNA regulation of AMPK in nonalcoholic fatty liver disease
Sun Hao,Kemper Jongsook Kim 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Obesity-associated nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is the leading cause of liver failure and death. The function of AMP-activated protein kinase (AMPK), a master energy sensor, is aberrantly reduced in NAFLD, but the underlying mechanisms are not fully understood. Increasing evidence indicates that aberrantly expressed microRNAs (miRs) are associated with impaired AMPK function in obesity and NAFLD. In this review, we discuss the emerging evidence that miRs have a role in reducing AMPK activity in NAFLD and nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. We also discuss the underlying mechanisms of the aberrant expression of miRs that can negatively impact AMPK, as well as the therapeutic potential of targeting the miR-AMPK pathway for NAFLD/NASH.
Choi, Sung E.,Kwon, Sanghoon,Seok, Sunmi,Xiao, Zhen,Lee, Kwan-Woo,Kang, Yup,Li, Xiaoling,Shinoda, Kosaku,Kajimura, Shingo,Kemper, Byron,Kemper, Jongsook Kim American Society for Microbiology 2017 Molecular and cellular biology Vol.37 No.15
<P>Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase 2 (CK2), the levels of which were dramatically elevated in obesity. Mechanistically, phosphorylation of SIRT1 at Ser-164 substantially inhibited its nuclear localization and modestly affected its deacetylase activity. Adenovirus-mediated liver-specific expression of SIRT1 or a phosphor-defective S164A-SIRT1 mutant promoted fatty acid oxidation and ameliorated liver steatosis and glucose intolerance in diet-induced obese mice, but these beneficial effects were not observed in mice expressing a phosphor-mimic S164D-SIRT1 mutant. Remarkably, phosphorylated S164-SIRT1 and CK2 levels were also highly elevated in liver samples of NAFLD patients and correlated with disease severity. Thus, inhibition of phosphorylation of SIRT1 by CK2 may serve as a new therapeutic approach for treatment of NAFLD and other obesity-related diseases.</P>