@article{96d58d5d47a94baf8b74d1b21acf23b3,
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.",
author = "Romeo Papazyan and Zheng Sun and Kim, {Yong Hoon} and Titchenell, {Paul M.} and Hill, {David A.} and Wenyun Lu and Manashree Damle and Min Wan and Yuxiang Zhang and Briggs, {Erika R.} and Rabinowitz, {Joshua D.} and Lazar, {Mitchell A.}",
note = "Funding Information: We thank T.F. Osborne (Sanford, Burnham, Prebys Institute) for the SCAP floxed mice backcrossed to the C57BL/6J genetic background. We thank the Viral Vector Core, Functional Genomics Core, and Princeton Regional Metabolomics Core of the Penn Diabetes Research Center (P30 DK19525), and the Penn Digestive Diseases Center Morphology Core (P30 DK050306). Deuterium-labeled palmitate levels were measured by the IDOM Metabolic Tracer Resource (J. Millar). We thank Q. Chu, Y.H. Foong, W. Teng, A. Angueira, and other members of the M.A.L. lab for technical support and S. Hackett (Princeton University) for assistance with statistical analysis of lipidomics data. This work was supported by NIH grants R37 DK43806 (M.A.L.), F32 DK108555 (R.P.), R00 DK099443 (Z.S.), F32 DK101175 (P.M.T.), and T32 GM008216 (Y.H.K), and the JPB Foundation. M.A.L. is on the scientific advisory boards for Pfizer Inc. and Eli Lilly and Company, and M.W. is currently employed at Agios Pharmaceuticals. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = dec,
day = "13",
doi = "10.1016/j.cmet.2016.10.012",
language = "English (US)",
volume = "24",
pages = "863--874",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}