Ketogenesis prevents diet‐induced fatty liver injury and hyperglycemia through coenzyme A recycling (LB769)

Abstract

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately one billion individuals worldwide. The mechanisms driving progressive steatohepatitis remain incompletely defined. Here we use a murine model of mitochondrial 3‐hydroxymethylglutaryl CoA synthase (HMGCS2)‐deficiency (using anti‐sense oligonucleotides) to demonstrate a critical role for ketogenesis in prevention of diet‐induced steatohepatitis. Adult‐onset loss of HMGCS2 caused mild hyperglycemia and increased hepatic gluconeogenesis from pyruvate in chow‐fed mice. High‐fat diet (HFD) feeding of ketogenesis insufficient mice caused extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic tricarboxylic acid (TCA) cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to fatty acid‐induced sequestration of coenzyme A (CoASH). CoASH precursor supplementation (pantothenic acid and cysteine) normalized TCA intermediates and gluconeogenesis in ketogenesis insufficient livers. These findings identify ketogenesis as a critical regulator of hepatic glucose metabolism and TCA cycle function via coordination of CoASH homeostasis in the absorptive state and indicate that ketogenesis modulates fatty liver disease.Grant Funding Source: HG00668702, DK091538, DK020579, DK056341, HL007873