Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia
David G. Cotter, … , Gary J. Patti, Peter A. Crawford
David G. Cotter, … , Gary J. Patti, Peter A. Crawford
Published December 1, 2014; First published October 27, 2014
Citation Information: J Clin Invest. 2014;124(12):5175-5190. https://doi.org/10.1172/JCI76388.
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Categories: 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 5

Altered DNL signatures in ketogenesis-insufficient mice.

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Altered DNL signatures in ketogenesis-insufficient mice. (A) Transcript ...
(A) Transcript abundances of DNL mediators in livers from ASO-treated mice. n = 5–10/group. Srebp1c, sterol regulatory element–binding protein 1c; Chrebp1, carbohydrate-responsive element-binding protein 1; Fasn, fatty acid synthase; Acc1, acetyl-CoA carboxylase; Scd1 and Scd2, stearoyl-CoA desaturase 1 and 2. (B) XCMS Online cloud plot of 495 dysregulated features in HMGCS2 ASO–treated livers perfused with [13C]pyruvate and [13C]lactate compared with those of control livers. The radius (upregulated and downregulated features relative to controls are green and red, respectively) and shading darkness of each circle are proportional to each circle’s fold-change and P value, respectively. n = 4/group. (C) Schematic adapted from the KEGG (refs. 38, 39), depicting the 14- and 16-carbon-long intermediates produced during fatty acid synthesis. Species putatively identified as features that are significantly enriched in HMGCS2 ASO–perfused livers are highlighted in green. (D) Untargeted LC/MS metabolomics identification and quantification of total abundance of long-chain acyl-CoA species in the livers of ASO-treated mice perfused with [13C]pyruvate and [13C]lactate. n = 4/group. (E) Quantification of fractional 13C enrichment of glutamate from [13C]pyruvate determined by NMR in extracts of perfused livers of ASO-treated mice. n = 7–8/group. (F) Relative acetyl-CoA ion counts in the livers of ASO-treated mice perfused with lactate and pyruvate as measured by LC/MS. n = 4/group. *P < 0.05, **P < 0.01, ***P < 0.001 by Student’s t test or 2-way ANOVA, as appropriate, versus HMGCS2 ASO–treated mice, or as indicated.