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Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration

Nature Medicine volume 18, pages 934–942 (2012)Cite this article

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Abstract

Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body weight compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose production. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2–coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metabolism.

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Figure 1: Liver-specific depletion of Hdac3 in adult mice causes quick-onset hepatosteatosis that is distinct from that caused by a HFD.
Figure 2: The Hdac3-depleted liver has impaired glucose production and is insulin hypersensitive.
Figure 3: Molecular insulin signaling events are unchanged despite lipid accumulation in the Hdac3-depleted liver.
Figure 4: Loss of Hdac3 reroutes precursors toward lipid synthesis and sequestration within lipid droplets.
Figure 5: Reduced hepatic glucose production in the Hdac3-depleted liver is a result of metabolic rerouting rather than inherent defects of gluconeogenesis.
Figure 6: Lipid sequestration is required for the development of severe hepatosteatosis and improved glucose tolerance in mice without hepatic Hdac3.

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Acknowledgements

We thank J. Millar and the Metabolic Tracer Resource at the Penn Institute for Diabetes, Obesity and Metabolism for the lipogenesis flux assay. We thank the Mouse Metabolic Phenotyping Core and the Viral Vector Core at Penn Diabetes Research Center (P30 DK19525) and the Penn Digestives Disease Center Morphology Core (P30 DK050306) at the University of Pennsylvania. We thank the Vanderbilt (DK59637) and Yale (U24 DK059635) Mouse Metabolic Phenotyping Centers and the Children's Hospital of Philadelphia Pathology Core. We thank B. Agarwal and S. Mullican for helpful discussion. This work was supported by US National Institutes of Health grants R37 DK43806 (M.A.L.), P01 DK49210 (M.A.L., M.J. Birnbaum and R.S.A.) and R01 DK40936 (G.I.S.), R01 DK075017 (C.S.), the Department of Veteran Affairs Merit Review Program (T.G.U.), grant F32 DK079572 (R.A.M.), the JPB Foundation and the Cox Institute for Medical Research.

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Authors and Affiliations

  1. Division of Endocrinology, Department of Medicine, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Zheng Sun, Russell A Miller, Rajesh T Patel, Ravindra Dhir, Rexford S Ahima, Morris J Birnbaum & Mitchell A Lazar

  2. The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Zheng Sun, Russell A Miller, Rajesh T Patel, Ravindra Dhir, Rexford S Ahima, Morris J Birnbaum & Mitchell A Lazar

  3. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Jie Chen & Michael J Bennett

  4. Division of Endocrinology, Department of Medicine, The Geriatric Research, Education and Clinical Center, Baltimore Veterans Affairs Health Care Center, School of Medicine, University of Maryland, Baltimore, Maryland, USA

    Hong Wang & Carole Sztalryd

  5. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Dongyan Zhang & Gerald I Shulman

  6. Isis Pharmaceuticals, Inc., Carlsbad, California, USA

    Mark J Graham

  7. Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

    Terry G Unterman

  8. Jesse Brown Virginia Medical Center, Chicago, Illinois, USA

    Terry G Unterman

  9. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael J Bennett

  10. Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Mitchell A Lazar

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  1. Zheng Sun
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Contributions

Z.S. and M.A.L. conceived of the hypothesis and designed the experiments. Z.S., R.A.M., R.T.P., J.C., R.D., H.W. and D.Z. performed the experiments. Z.S., R.A.M., R.D., T.G.U., G.I.S., C.S., M.J. Bennett, R.S.A., M.J. Birnbaum and M.A.L. analyzed and interpreted the data. M.J.G. provided reagents. Z.S. and M.A.L. wrote the manuscript.

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Correspondence to Mitchell A Lazar.

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Sun, Z., Miller, R., Patel, R. et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med 18, 934–942 (2012). https://doi.org/10.1038/nm.2744

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