Induced Polymerization of Mammalian Acetyl-CoA Carboxylase by MIG12 Provides a Tertiary Level of Regulation of Fatty Acid Synthesis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 May 12

PMID 20457939

Citations 73

Authors

Chai-Wan Kim

Young-Ah Moon

Sahng Wook Park

Dong Cheng

Hyock Joo Kwon

Jay D Horton

Affiliations

Soon will be listed here.

Abstract

Acetyl-CoA carboxylase (ACC), the first committed enzyme in fatty acid (FA) synthesis, is regulated by phosphorylation/dephosphorylation, transcription, and an unusual mechanism of protein polymerization. Polymerization of ACC increases enzymatic activity and is induced in vitro by supraphysiological concentrations of citrate (> 5 mM). Here, we show that MIG12, a 22 kDa cytosolic protein of previously unknown function, binds to ACC and lowers the threshold for citrate activation into the physiological range (< 1 mM). In vitro, recombinant MIG12 induced polymerization of ACC (as determined by nondenaturing gels, FPLC, and electron microscopy) and increased ACC activity by > 50-fold in the presence of 1 mM citrate. In vivo, overexpression of MIG12 in liver induced ACC polymerization, increased FA synthesis, and produced triglyceride accumulation and fatty liver. Thus, in addition to its regulation by phosphorylation and transcription, ACC is regulated at a tertiary level by MIG12, which facilitates ACC polymerization and enhances enzymatic activity.

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