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      Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration

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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 by a variety of mechanisms. Here we show that mice with liver-specific deletion of histone deacetylase 3 (Hdac3) display severe hepatosteatosis and, notably increased insulin sensitivity without changes in insulin signaling or body weight. Hdac3 deletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets (LDs). Reduced hepatic glucose production in Hdac3-depleted liver is a result of the metabolic rerouting rather than due to inherently defective gluconeogenesis. The lipid-sequestering LDs-coating protein Perilipin 2 is markedly induced upon Hdac3 deletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids ameliorates insulin resistance, and establish Hdac3 as a pivotal epigenomic modifier that integrate signals from the circadian clock in regulation of hepatic intermediary metabolism.

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          Most cited references 43

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          Selective versus total insulin resistance: a pathogenic paradox.

          Mice with type 2 diabetes manifest selective hepatic insulin resistance: insulin fails to suppress gluconeogenesis but continues to activate lipogenesis, producing the deadly combination of hyperglycemia and hypertriglyceridemia. In this issue of Cell Metabolism, Biddinger et al. (2008) show that mice with total hepatic insulin resistance exhibit hyperglycemia without hypertriglyceridemia-a state paradoxically less severe than selective insulin resistance.
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            Molecular mediators of hepatic steatosis and liver injury.

            Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.
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              Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis.

              The majority of eukaryotic cells synthesize neutral lipids and package them into cytosolic lipid droplets. In vertebrates, triacylglycerol-rich lipid droplets of adipocytes provide a major energy storage depot for the body, whereas cholesteryl ester-rich droplets of many other cells provide building materials for local membrane synthesis and repair. These lipid droplets are coated with one or more of five members of the perilipin family of proteins: adipophilin, TIP47, OXPAT/MLDP, S3-12, and perilipin. Members of this family share varying levels of sequence similarity, lipid droplet association, and functions in stabilizing lipid droplets. The most highly studied member of the family, perilipin, is the most abundant protein on the surfaces of adipocyte lipid droplets, and the major substrate for cAMP-dependent protein kinase [protein kinase A (PKA)] in lipolytically stimulated adipocytes. Perilipin serves important functions in the regulation of basal and hormonally stimulated lipolysis. Under basal conditions, perilipin restricts the access of cytosolic lipases to lipid droplets and thus promotes triacylglycerol storage. In times of energy deficit, perilipin is phosphorylated by PKA and facilitates maximal lipolysis by hormone-sensitive lipase and adipose triglyceride lipase. A model is discussed whereby perilipin serves as a dynamic scaffold to coordinate the access of enzymes to the lipid droplet in a manner that is responsive to the metabolic status of the adipocyte.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                19 March 2012
                June 2012
                01 December 2012
                : 18
                : 6
                : 934-942
                Affiliations
                [1 ]Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
                [2 ]Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
                [3 ]The Geriatric Research, Education and Clinical Center, Baltimore Veterans Affairs Health Care Center, Division of Endocrinology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201
                [4 ]Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
                [5 ]Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
                [6 ]Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, and Jesse Brown VA Medical Center, Chicago, IL 60612, USA
                [7 ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
                Author notes
                Address Correspondence to: Mitchell A. Lazar, M.D., Ph.D., Phone: (215) 898-0198; lazar@ 123456mail.med.upenn.edu
                Article
                NIHMS364576
                10.1038/nm.2744
                3411870
                22561686

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                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R37 DK043806-22 || DK
                Categories
                Article

                Medicine

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