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.