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

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

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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