Acetylation of mitochondrial trifunctional protein α-subunit enhances its stability to promote fatty acid oxidation and is decreased in nonalcoholic fatty liver disease

Liang Guo, Shui Rong Zhou, Xiang Bo Wei, Yuan Liu, Xin Xia Chang, Yang Liu, Xin Ge, Xin Dou, Hai Yan Huang, Shu Wen Qian, Xi Li, Qun Ying Lei, Xin Gao, Qi Qun Tang

Research output: Contribution to journalArticle

Abstract

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 α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPα. Replacement of MTPα-3K with either MTPα-3KR or MTPα-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 MTPα-3K mutant expression in mouse livers, and MTPα-3K mutants more efficiently attenuate SIRT4- mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPα and MTPα-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPα regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

Original languageEnglish (US)
Pages (from-to)2553-2567
Number of pages15
JournalMolecular and Cellular Biology
Volume36
Issue number20
DOIs
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Guo, L., Zhou, S. R., Wei, X. B., Liu, Y., Chang, X. X., Liu, Y., Ge, X., Dou, X., Huang, H. Y., Qian, S. W., Li, X., Lei, Q. Y., Gao, X., & Tang, Q. Q. (2016). Acetylation of mitochondrial trifunctional protein α-subunit enhances its stability to promote fatty acid oxidation and is decreased in nonalcoholic fatty liver disease. Molecular and Cellular Biology, 36(20), 2553-2567. https://doi.org/10.1128/MCB.00227-16