title: Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.
abstract: Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide-induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.
authors.forename: David G
authors.initials: DG
authors.lastname: Cotter
authors.forename: Baris
authors.initials: B
authors.lastname: Ercal
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huang
authors.forename: Jamison M
authors.initials: JM
authors.lastname: Leid
authors.forename: D André
authors.initials: DA
authors.lastname: d'Avignon
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Dietzen
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Patti
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crawford
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects*; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000214:Acyl Coenzyme A; D004041:Dietary Fats; D006904:Hydroxymethylglutaryl-CoA Synthase; D005947:Glucose