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

  • Cell Metab. 2017 Aug 1;26(2):394-406.e6. doi: 10.1016/j.cmet.2017.07.009.
Chai-Wan Kim  1 ,  Carol Addy  2 ,  Jun Kusunoki  2 ,  Norma N Anderson  1 ,  Stanislaw Deja  3 ,  Xiaorong Fu  3 ,  Shawn C Burgess  3 ,  Cai Li  2 ,  Marcie Ruddy  2 ,  Manu Chakravarthy  2 ,  Steve Previs  2 ,  Stuart Milstein  4 ,  Kevin Fitzgerald  4 ,  David E Kelley  2 ,  Jay D Horton  5
Affiliations
  • 1. Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
  • 2. MRL, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
  • 3. Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA.
  • 5. Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. Electronic address: [email protected].
PMID: 28768177 DOI: 10.1016/j.cmet.2017.07.009
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.

Keywords
SREBPs; acetyl-CoA carboxylase; hepatic steatosis; hypertriglyceridemia; inhibitors; lipogenesis; malonyl-CoA.
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