Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

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

来源：Molecular and Cellular Biology, 2016, 36(20): 2553-2567.

DOI：10.1128/MCB.00227-16

• HEPATIC STEATOSIS
• LYSINE ACETYLATION
• INSULIN-RESISTANCE
• SIRT4
• STEATOHEPATITIS
• MICE
• UBIQUITINATION
• DEGRADATION
• METABOLISM
• PROTEASOME

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

• 出版日期2016-10-15
• 单位复旦大学