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

• Published in: Cell metabolism Vol. 26; no. 2; pp. 394 - 406.e6
• Main Authors: Kim, Chai-Wan, Addy, Carol, Kusunoki, Jun, Anderson, Norma N., Deja, Stanislaw, Fu, Xiaorong, Burgess, Shawn C., Li, Cai, Ruddy, Marcie, Chakravarthy, Manu, Previs, Steve, Milstein, Stuart, Fitzgerald, Kevin, Kelley, David E., Horton, Jay D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017
• Subjects: acetyl-CoA carboxylase; 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; hepatic steatosis; Hepatocytes - enzymology; Hepatocytes - pathology; Humans; hypertriglyceridemia; inhibitors; lipogenesis; Lipoproteins, VLDL - genetics; Lipoproteins, VLDL - secretion; malonyl-CoA; Mice; Mice, Knockout; SREBPs; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Triglycerides - blood; Triglycerides - genetics; inhibitors; malonyl-CoA; hypertriglyceridemia; SREBPs; lipogenesis; acetyl-CoA carboxylase; hepatic steatosis
• ISSN: 1550-4131; 1932-7420; 1932-7420
• 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. [Display omitted] •Inhibition of ACC in liver reduces lipogenesis and increases fatty acid oxidation•In humans with fatty livers, ACC inhibition reduces liver triglycerides•Deletion of ACCs depletes malonyl-CoA, reducing polyunsaturated fatty acid synthesis•Resulting activation of SREBP-1c increases GPAT1, leading to hypertriglyceridemia 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.