Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis

Chai Wan Kim, Young Ah Moon, Sahng Wook Park, Dong Cheng, Hyock Joo Kwon, Jay D. Horton

Research output: Contribution to journalArticle

71 Scopus citations

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 FAsynthesis, and produced triglyceride accumulationandfatty 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.

Original languageEnglish (US)
Pages (from-to)9626-9631
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number21
DOIs
StatePublished - May 25 2010

Keywords

  • Lipogenesis
  • Srebps
  • Steatosis

ASJC Scopus subject areas

  • General

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