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.


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.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Enzyme Inhibitors / pharmacology*
  • Fatty Liver / blood*
  • Fatty Liver / drug therapy*
  • Fatty Liver / genetics
  • Fatty Liver / pathology
  • Hepatocytes / enzymology
  • Hepatocytes / pathology
  • Humans
  • Lipoproteins, VLDL / genetics
  • Lipoproteins, VLDL / metabolism
  • Mice
  • Mice, Knockout
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Triglycerides / blood*
  • Triglycerides / genetics


  • Enzyme Inhibitors
  • Lipoproteins, VLDL
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • ACACA protein, human
  • ACACB protein, human
  • ACC1 protein, mouse
  • Acacb protein, mouse
  • Acetyl-CoA Carboxylase