Σφακιανάκης Αλέξανδρος
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Τρίτη 1 Αυγούστου 2017

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

Publication date: 1 August 2017
Source:Cell Metabolism, Volume 26, Issue 2
Author(s): 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
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.

Graphical abstract

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Teaser

Kim et al. describe an inhibitor of acetyl-CoA carboxylase (ACC) 1 and 2 that reduces liver triglycerides in individuals with fatty livers, but increases plasma triglycerides. In mice lacking ACCs, reduced malonyl-CoA levels suppress polyunsaturated fatty acid synthesis, leading to increased SREBP-1c and GPAT1 expression, increased VLDL secretion, and hypertriglyceridemia.


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