| First Author | Guo L | Year | 2016 |
| Journal | Mol Cell Biol | Volume | 36 |
| Issue | 20 | Pages | 2553-67 |
| PubMed ID | 27457618 | Mgi Jnum | J:236308 |
| Mgi Id | MGI:5805720 | Doi | 10.1128/MCB.00227-16 |
| Citation | Guo L, et al. (2016) Acetylation of Mitochondrial Trifunctional Protein alpha-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease. Mol Cell Biol 36(20):2553-67 |
| abstractText | Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein alpha-subunit (MTPalpha) functions as a critical enzyme for fatty acid beta-oxidation, but whether dysregulation of MTPalpha is pathogenically connected to NAFLD is poorly understood. We show that MTPalpha is acetylated at lysine residues 350, 383, and 406 (MTPalpha-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPalpha-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPalpha. Replacement of MTPalpha-3K with either MTPalpha-3KR or MTPalpha-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPalpha-3K mutant expression in mouse livers, and MTPalpha-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPalpha and MTPalpha-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPalpha regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD. |
