Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice

• Published in: Journal of lipid research 2018-06, Vol.59 (6), p.967-973
• Main Authors: Nassir, Fatiha, Arndt, Justin J., Johnson, Sarah A., Ibdah, Jamal A.
• Format: Article
• Language: English
• Subjects: Acetylation; Adenine; Aging; Animals; Deacetylation; Diet, High-Fat - adverse effects; Fatty acids; Fatty Acids - metabolism; Fatty liver; High fat diet; Immunoprecipitation; Inflammation; Liver - metabolism; Liver diseases; Lysine; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; mitochondrial trifunctional protein; Mitochondrial Trifunctional Protein - deficiency; Mitochondrial Trifunctional Protein - metabolism; NAD; Nicotinamide; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oxidation; Oxidation-Reduction; Post-transcription; Proteins; Rodents; sirtuin 3; Sirtuin 3 - metabolism; Steatosis; Triglycerides - metabolism; β-Galactosidase
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M080952

Mitochondrial trifunctional protein (MTP) plays a critical role in the oxidation of long-chain fatty acids. We previously reported that aging mice (>9 months old) heterozygous for an MTP defect (MTP+/−) develop nonalcoholic fatty liver disease (NAFLD). We tested whether a high-fat diet (HFD) accelerates NAFLD in young MTP+/−mice, and whether overexpression of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 3 (SIRT3) deacetylates MTP and improves mitochondrial function and NAFLD. Three-month-old WT and MTP+/− mice were fed HFD (60% cal fat) for 16 weeks and livers were assessed for fatty acid oxidation (FAO) and NAFLD. Compared with WT, MTP+/− mice displayed reduced hepatic SIRT3 levels and reduced FAO, with increased hepatic steatosis and the inflammatory marker CD68. Hepatic overexpression of SIRT3 in HFD-fed MTP+/− mice increased hepatic MTP protein levels at the posttranscriptional level. Immunoprecipitation of MTP from liver mitochondria followed by Western blot with acetyl-lysine antibody showed higher acetylation of MTP in MTP+/− compared with WT mice. Overexpression of SIRT3 in MTP+/− mice significantly reduced the acetylation of MTP compared with β-galactosidase controls, increased mitochondrial FAO, and reduced hepatic steatosis, CD68, and serum ALT levels. Taken together, our data indicate that deacetylation of MTP by SIRT3 improves mitochondrial function and rescues NAFLD in MTP+/− mice.