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JCI Insight. 2018 Jun 21;3(12). pii: 99762. doi: 10.1172/jci.insight.99762. eCollection 2018 Jun 21.

Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome.

Author information

1
Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
2
Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
3
Department of Psychiatry, Washington University, St. Louis, Missouri, USA.
4
Pathobiology Graduate Program, Brown University, Providence, Rhode Island, USA.
5
Ionis Pharmaceuticals, Carlsbad, California, USA.
6
Department of Chemistry, Washington University, St. Louis, Missouri, USA.
7
Barshop Institute for Longevity and Aging Studies, Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
8
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.

Abstract

While several molecular targets are under consideration, mechanistic underpinnings of the transition from uncomplicated nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) remain unresolved. Here we apply multiscale chemical profiling technologies to mouse models of deranged hepatic ketogenesis to uncover potential NAFLD driver signatures. Use of stable-isotope tracers, quantitatively tracked by nuclear magnetic resonance (NMR) spectroscopy, supported previous observations that livers of wild-type mice maintained long term on a high-fat diet (HFD) exhibit a marked increase in hepatic energy charge. Fed-state ketogenesis rates increased nearly 3-fold in livers of HFD-fed mice, a greater proportionate increase than that observed for tricarboxylic acid (TCA) cycle flux, but both of these contributors to overall hepatic energy homeostasis fueled markedly increased hepatic glucose production (HGP). Thus, to selectively determine the role of the ketogenic conduit on HGP and oxidative hepatic fluxes, we studied a ketogenesis-insufficient mouse model generated by knockdown of the mitochondrial isoform of 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In response to ketogenic insufficiency, TCA cycle flux in the fed state doubled and HGP increased more than 60%, sourced by a 3-fold increase in glycogenolysis. Finally, high-resolution untargeted metabolomics and shotgun lipidomics performed using ketogenesis-insufficient livers in the fed state revealed accumulation of bis(monoacylglycero)phosphates, which also accumulated in livers of other models commonly used to study NAFLD. In summary, natural and interventional variations in ketogenesis in the fed state strongly influence hepatic energy homeostasis, glucose metabolism, and the lipidome. Importantly, HGP remains tightly linked to overall hepatic energy charge, which includes both terminal fat oxidation through the TCA cycle and partial oxidation via ketogenesis.

KEYWORDS:

Fatty acid oxidation; Glucose metabolism; Hepatology; Metabolism; Mouse models

PMID:
29925686
PMCID:
PMC6124396
DOI:
10.1172/jci.insight.99762
[Indexed for MEDLINE]
Free PMC Article

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