Inhibition of mitochondrial β-oxidation by miR-107 promotes hepatic lipid accumulation and impairs glucose tolerance in vivo

• Published in: International Journal of Obesity 2016-05, Vol.40 (5), p.861-869
• Main Authors: Bhatia, H, Pattnaik, B R, Datta, M
• Format: Article
• Language: English
• Subjects: 13/95; 14/1; 38; 631/337/384/331; 631/443/319/1642/393; 631/443/319/2723; 631/45/287/1183; 631/80/642/1463; 692/699/317; Accumulation; Animals; Apolipoproteins; Blotting, Western; Body weight; Butyric acid; Cells, Cultured; Cholesterol; Disease Models, Animal; Droplets; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Enoyl-CoA hydratase; Epidemiology; Fatty acids; Fatty Acids - metabolism; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty-acid synthase; Gene Expression Regulation; Genes; Genetic aspects; Genetic transcription; Glucose; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose tolerance; Glutamic oxaloacetic transaminase; Health aspects; Health Promotion and Disease Prevention; Hepatocytes; Hepatocytes - metabolism; Humans; Hyperglycemia; Immunohistochemistry; In vivo methods and tests; Internal Medicine; Lipid Metabolism; Lipids; Lipogenesis - physiology; Liver; Liver - metabolism; Liver - pathology; Male; Medicine; Medicine & Public Health; Membrane proteins; Metabolic Diseases; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; original-article; Oxidation; Oxidation-Reduction; Properties; Public Health; Reverse transcription; Ribonucleic acid; RNA; Serum levels; siRNA; Thiolase; Transaminase; Transcription factors; Triglycerides; Tunicamycin
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2015.225

Background: Hepatic expression of microRNA-107 is ubiquitously upregulated in various metabolic diseases. In our previous study, we had demonstrated that fatty acid synthase (FASN) is a target of miR-107. miR-107-FASN interaction, by inducing endoplasmic reticulum (ER) stress, promotes lipid accumulation in hepatocytes. Here, we explore the possible mechanism(s) of the miR-107-FASN-ER stress on hepatic lipid metabolism. Methods: HepG2 cells were transfected with the scramble or miR-107 and/or its inhibitor. Transcript levels of lipid droplet membrane proteins, apolipoproteins and β-oxidation genes were quantified by quantitative reverse transcription-PCR. Cells were treated with tunicamycin (Tm, 1 h) and 4-PBA (4-phenyl butyric acid, 8 h) or transfected with hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, apha subunit (HADHA) short interfering RNA or its overexpression vector. Mice were injected with the scramble or mmu-miR-107 (2.5 mg kg −1 body weight) and random glucose levels were measured and oral glucose tolerance test was performed. Serum levels of cholesterol, triglyceride and serum glutamic oxaloacetic transaminase/serum glutamic-pyruvic transaminase (SGOT/SGPT) were evaluated. Hepatic tissues were collected to estimate levels of miR-107 and mitochondrial β-oxidation genes. Six-micrometer-thick cryosections of hepatic tissues were prepared and stained with Oil Red O for lipid accumulation. Results: miR-107 does not alter the expression of lipid metabolism-related transcription factors, lipid droplet components and apolipiprotein B. miR-107 significantly decreased the levels of the mitochondrial β-oxidation enzyme, HADHA in HepG2 cells ( P