title: Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease.
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.
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Shui-Rong
authors.initials: SR
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Xiang-Bo
authors.initials: XB
authors.lastname: Wei
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Fudan University Zhongshan Hospital, Shanghai, People's Republic of China.
authors.forename: Xin-Xia
authors.initials: XX
authors.lastname: Chang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ge
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dou
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Qian
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
authors.affiliation: Department of Endocrinology and Metabolism, Fudan University Zhongshan Hospital, Shanghai, People's Republic of China happy20061208@126.com qqtang@shmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China happy20061208@126.com qqtang@shmu.edu.cn.
authors.forename: Qi-Qun
authors.initials: QQ
authors.lastname: Tang
mesh_terms: D000107:Acetylation; D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063992:Mitochondrial Trifunctional Protein, alpha Subunit / Q000737:chemistry* / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D010084:Oxidation-Reduction; D055550:Protein Stability; D037761:Sirtuins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D005227:Fatty Acids; D024101:Mitochondrial Proteins; D063992:Mitochondrial Trifunctional Protein, alpha Subunit; C514813:SIRT4 protein, mouse; D037761:Sirtuins; D008239:Lysine