Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia
David G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, Peter A. Crawford
David G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, Peter A. Crawford
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Research Article Hepatology

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

David G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, Peter A. Crawford

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Figure 8

Model of hepatic maladaptation to ketogenic insufficiency.

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Model of hepatic maladaptation to ketogenic insufficiency. Under homeost...
Under homeostatic conditions (left panel), mitochondrial acetyl-CoA can be channeled to ketogenesis, terminal oxidation in the TCA cycle, or exported to the cytoplasm for DNL. In the setting of ketogenic insufficiency (middle panel), DNL and gluconeogenesis from pyruvate are increased. Loss of the ketogenic conduit stimulates increased acetyl-CoA disposal through the TCA cycle, increasing gluconeogenesis and export to the cytoplasm for DNL. These changes partly reflect the alterations encountered in NAFLD, in which the liver exhibits increased esterification to and lipolysis from lipid droplets, increased β-oxidation of fatty acids, increased terminal oxidation, and increased gluconeogenesis, but diminished ketogenesis relative to the availability of fat. In the extreme circumstance of ketogenic insufficiency and a high-fat load (right panel), β-oxidation–derived acetyl-CoA sequesters CoASH. This disrupts the TCA cycle, and in the setting of increased DNL, ultimately triggers hepatic injury and inflammation. Arrow thicknesses reflect relative changes through enzymatic reactions among panels rather than between reaction pathways within a panel. While proportional contributions of pyruvate carboxylase (PC) and PDH fluxes to the pyruvate fate are dynamic in states of feeding and fasting, both fluxes occur simultaneously in both physiological states (86, 87) and are likely to be influenced by insufficient ketogenesis. ME, malic enzyme.