title: Induction of miR-96 by Dietary Saturated Fatty Acids Exacerbates Hepatic Insulin Resistance through the Suppression of INSR and IRS-1.
abstract: Obesity is defined as the excessive accumulation of body fat that ultimately leads to chronic metabolic diseases. Diets rich in saturated fatty acids (SFA) exacerbate obesity and hepatic steatosis, which increase the risk of hepatic insulin resistance and type 2 diabetes (T2DM). Although microRNAs (miRNAs) play an important role in a range of biological processes, the implications of SFA-induced miRNAs in metabolic dysregulation, particularly in the pathogenesis of hepatic insulin resistance, are not well understood. This study investigated the implications of miR-96, which is induced strongly by SFA, in the development of hepatic insulin resistance. The liver of HFD mice and the palmitate-treated hepatocytes exhibited an impairment of insulin signaling due to the significant decrease in INSR and IRS-1 expression. According to expression profiling and qRT-PCR analysis of the miRNAs, the expression level of miR-96 was higher in hepatocytes treated with palmitate. Moreover, miR-96 was also upregulated in the liver of HFD mice. Interestingly, miR-96 targeted the 3'UTRs of INSR and IRS-1 directly, and repressed the expression of INSR and IRS-1 at the post-transcriptional level. Accordingly, the overexpression of miR-96 was found to cause a significant decrease in INSR and IRS-1 expression, thereby leading to an impairment of insulin signaling and glycogen synthesis in hepatocytes. These results reveal a novel mechanism whereby miR-96 promotes the pathogenesis of hepatic insulin resistance resulted from SFA or obesity.
authors.affiliation: Department of Biochemistry, Dongguk University College of Medicine, Gyeongju, Korea.
authors.forename: Won-Mo
authors.initials: WM
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Dongguk University College of Medicine, Gyeongju, Korea.
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Min
authors.affiliation: Department of Biochemistry, Dongguk University College of Medicine, Gyeongju, Korea.|Endocrine Channelopathy, Channelopathy Research Center, Dongguk University College of Medicine, Goyang, Korea.
authors.forename: Wan
authors.identifier: http://orcid.org/0000-0002-5181-2135
authors.initials: W
authors.lastname: Lee
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000494:pharmacology; D005234:Fatty Liver / Q000473:pathology; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis* / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009765:Obesity / Q000473:pathology*; D010168:Palmitates / Q000378:metabolism; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; D005227:Fatty Acids; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D035683:MicroRNAs; C541554:Mirn96 microRNA, mouse; D010168:Palmitates; C435941:INSR protein, human; D011972:Receptor, Insulin