MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN

Approximately 15-40% of the general adult population suffers from non-alcoholic fatty liver disease (NAFLD) worldwide. However, no drug is currently licensed for its treatment. In this study, we observed a significant reduction of miR-30c-5p in the liver of leptin receptor-deficient (db/db) mice. Remarkably, recombinant adeno-associated virus (rAAV)-mediated delivery of miR-30c-5p was sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice. Through computational prediction, KEGG analysis and Ago2 co-immunoprecipitation, we identified that miR-30c-5p directly targeted fatty acid synthase, a key enzyme in fatty acid biosynthesis. Moreover, down-regulation of FASN by siRNA attenuated some key features of NAFLD, including decreased triglyceride accumulate and lipid deposition. Our findings reveal a new role of miR-30c-5p in counterbalancing fatty acid biosynthesis, which is sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice.

[1]  V. Wong,et al.  A LEAN treatment for non-alcoholic steatohepatitis , 2016, The Lancet.

[2]  Daowen Wang,et al.  miR ‐ 320 a mediates doxorubicin ‐ induced cardiotoxicity by targeting , 2016 .

[3]  Daowen Wang,et al.  Identification of cardiac-related circulating microRNA profile in human chronic heart failure , 2015, Oncotarget.

[4]  Tao Wang,et al.  Negative correlation of ITCH E3 ubiquitin ligase and miRNA-106b dictates metastatic progression in pancreatic cancer , 2015, Oncotarget.

[5]  Q. Tang,et al.  Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice. , 2015, Journal of hepatology.

[6]  Chunxia Wang,et al.  Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy , 2015, Diabetes.

[7]  W. Liu,et al.  ‘Micro‐managers’ of hepatic lipid metabolism and NAFLD , 2015, Wiley interdisciplinary reviews. RNA.

[8]  V. Wong,et al.  Prevalence and Severity of Nonalcoholic Fatty Liver Disease in Non-Obese Patients: A Population Study Using Proton-Magnetic Resonance Spectroscopy , 2015, The American Journal of Gastroenterology.

[9]  Artemis G. Hatzigeorgiou,et al.  DIANA-miRPath v3.0: deciphering microRNA function with experimental support , 2015, Nucleic Acids Res..

[10]  J. Loor,et al.  Short communication: Effect of inhibition of fatty acid synthase on triglyceride accumulation and effect on lipid metabolism genes in goat mammary epithelial cells. , 2015, Journal of dairy science.

[11]  Philippe Lefebvre,et al.  Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. , 2015, Journal of hepatology.

[12]  Mingshi Yang,et al.  miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. , 2015, International journal of molecular medicine.

[13]  Lei Yang,et al.  MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF , 2015, Journal of cellular and molecular medicine.

[14]  Shuping Xiao,et al.  miRNA functional synergistic network analysis of mice with ischemic stroke , 2014, Neurological Sciences.

[15]  C. Fernández-Hernando,et al.  MicroRNA-30c reduces hyperlipidemia and atherosclerosis by decreasing lipid synthesis and lipoprotein secretion , 2012, Nature Medicine.

[16]  Zhihua Jiang,et al.  Coordinated miRNA/mRNA Expression Profiles for Understanding Breed-Specific Metabolic Characters of Liver between Erhualian and Large White Pigs , 2012, PloS one.

[17]  Stefan L Ameres,et al.  Long-term, efficient inhibition of microRNA function in mice using rAAV vectors , 2012, Nature Methods.

[18]  Giorgio Saracco,et al.  The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study , 2011, Hepatology.

[19]  Margaret S. Wu,et al.  Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes , 2011, Proceedings of the National Academy of Sciences.

[20]  E. van Rooij.  The art of microRNA research. , 2011, Circulation Research.

[21]  M. Odenthal,et al.  Combined paracrine and endocrine AAV9 mediated expression of hepatocyte growth factor for the treatment of renal fibrosis. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  Robert V Farese,et al.  Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids , 2009, Hepatology.

[23]  E. Olson,et al.  MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. , 2007, The Journal of clinical investigation.

[24]  K. Kotoh,et al.  Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. , 2007, International journal of molecular medicine.

[25]  N. Ban,et al.  Architecture of mammalian fatty acid synthase , 2006 .

[26]  Timm Maier,et al.  Architecture of Mammalian Fatty Acid Synthase at 4.5 Å Resolution , 2006, Science.

[27]  James Z. Chadick,et al.  Structure and molecular organization of mammalian fatty acid synthase , 2005, Nature Structural &Molecular Biology.

[28]  S. Chirala,et al.  Structure and function of animal fatty acid synthase , 2004, Lipids.

[29]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[30]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[31]  Robert V Farese,et al.  Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. , 2002, The Journal of clinical investigation.

[32]  G. Lewis,et al.  Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. , 2002, Endocrine reviews.

[33]  Robert V Farese,et al.  Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.