title: Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP.
abstract: Liver fat accumulation precedes non-alcoholic steatohepatitis, an increasing cause of end-stage liver disease. Histone deacetylase 3 (HDAC3) is required for hepatic triglyceride homeostasis, and sterol regulatory element binding protein (SREBP) regulates the lipogenic response to feeding, but the crosstalk between these pathways is unknown. Here we show that inactivation of SREBP by hepatic deletion of SREBP cleavage activating protein (SCAP) abrogates the increase in lipogenesis caused by loss of HDAC3, but fatty acid oxidation remains defective. This combination leads to accumulation of lipid intermediates and to an energy drain that collectively cause oxidative stress, inflammation, liver damage, and, ultimately, synthetic lethality. Remarkably, this phenotype is prevented by ectopic expression of nuclear SREBP1c, revealing a surprising benefit of de novo lipogenesis and triglyceride synthesis in preventing lipotoxicity. These results demonstrate that HDAC3 and SCAP control symbiotic pathways of liver lipid metabolism that are critical for suppression of lipotoxicity.
authors.affiliation: 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.
authors.forename: Romeo
authors.initials: R
authors.lastname: Papazyan
authors.affiliation: 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; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Yong Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Titchenell
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Hill
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Wenyun
authors.initials: W
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Manashree
authors.initials: M
authors.lastname: Damle
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Wan
authors.affiliation: 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.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Erika R
authors.initials: ER
authors.lastname: Briggs
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: 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. Electronic address: lazar@mail.med.upenn.edu.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D001483:Base Sequence; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D008055:Lipids / Q000633:toxicity*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D005227:Fatty Acids; D005947:Glucose; D006655:Histone Deacetylases; D008055:Lipids; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D000099186:Histone Deacetylase 3