title: Enzymatic and transcriptional regulation of the cytoplasmic acetyl-CoA hydrolase ACOT12.
abstract: Acyl-CoA thioesterase 12 (ACOT12) is the major enzyme known to hydrolyze the thioester bond of acetyl-CoA in the cytosol in the liver. ACOT12 contains a catalytic thioesterase domain at the N terminus and a steroidogenic acute regulatory protein-related lipid transfer (START) domain at the C terminus. We investigated the effects of lipids (phospholipids, sphingolipids, fatty acids, and sterols) on ACOT12 thioesterase activity and found that the activity was inhibited by phosphatidic acid (PA) in a noncompetitive manner. In contrast, the enzymatic activity of a mutant form of ACOT12 lacking the START domain was not inhibited by the lipids. These results suggest that the START domain is important for regulation of ACOT12 activity by PA. We also found that PA could bind to thioesterase domain, but not to the START domain, and had no effect on ACOT12 dissociation. ACOT12 is detectable in the liver but not in hepatic cell lines such as HepG2, Hepa-1, and Fa2N-4. ACOT12 mRNA and protein levels in rat primary hepatocytes decreased following treatment with insulin. These results suggest that cytosolic acetyl-CoA levels in the liver are controlled by lipid metabolites and hormones, which result in allosteric enzymatic and transcriptional regulation of ACOT12.
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Horibata
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Biochemistry, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan. Electronic address: h-sugi@dokkyomed.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
mesh_terms: D000104:Acetyl-CoA Hydrolase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D003593:Cytoplasm / Q000201:enzymology*; D007328:Insulin / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D010712:Phosphatidic Acids / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*
chemical_list: D007328:Insulin; D008055:Lipids; D010712:Phosphatidic Acids; D012333:RNA, Messenger; D000104:Acetyl-CoA Hydrolase
keywords: acyl-CoA thioesterase 12; lipid biosynthesis; phosphatidic acid; steroidogenic acute regulatory protein-related lipid transfer domain protein