Abstract
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.
Highlights
Mitochondrial trifunctional protein (MTP) plays a critical role in the oxidation of long-chain fatty acids
The increase in hepatic triglyceride in MTP+/ mice was associated with >50% reduction in fatty acid oxidation (FAO) compared with WT (Fig. 1C)
MTP is a multienzyme protein complex that plays a major role in mitochondrial FAO as it carries three of the four enzymes required for long-chain FAO
Summary
Mitochondrial trifunctional protein (MTP) plays a critical role in the oxidation of long-chain fatty acids. 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. Overexpression of SIRT3 in MTP+/ mice significantly reduced the acetylation of MTP compared with -galactosidase controls, increased mitochondrial FAO, and reduced hepatic steatosis, CD68, and serum ALT levels. Apart from life style modifications such as calorie restriction and exercise, no effective pharmacological treatment currently exists to treat NAFLD [7, 11] This is mainly due to the lack of clear understanding of the underlying pathophysiology of the disease. Mitochondrial dysfunction is a common finding in NAFLD patients and in animal models of NAFLD where ultrastructural abnormalities of liver mitochondria, reduced FAO, impaired hepatic ATP synthesis, reduced respiration, and increased oxidative stress have been observed [2, 5, 12,13,14,15,16,17]
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