Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation

Chai Wan Kim, Carol Addy, Jun Kusunoki, Norma N. Anderson, Stanislaw Deja, Xiaorong Fu, Shawn C. Burgess, Cai Li, Manu Chakravarthy, Steve Previs, Stuart Milstein, Kevin Fitzgerald, David E. Kelley, Jay D. Horton

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.

Original languageEnglish (US)
Pages (from-to)394-406.e6
JournalCell Metabolism
Volume26
Issue number2
DOIs
StatePublished - Aug 1 2017

Keywords

  • SREBPs
  • acetyl-CoA carboxylase
  • hepatic steatosis
  • hypertriglyceridemia
  • inhibitors
  • lipogenesis
  • malonyl-CoA

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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