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Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP.
- Source :
-
Cell metabolism [Cell Metab] 2016 Dec 13; Vol. 24 (6), pp. 863-874. Date of Electronic Publication: 2016 Nov 17. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Base Sequence
Fatty Acids metabolism
Fatty Liver genetics
Fatty Liver pathology
Glucose pharmacology
Inflammation pathology
Lipogenesis drug effects
Lipogenesis genetics
Liver drug effects
Mice, Inbred C57BL
Mice, Knockout
Oxidation-Reduction drug effects
Oxidative Stress drug effects
Protein Binding drug effects
Protein Binding genetics
Transcription, Genetic drug effects
Triglycerides metabolism
Histone Deacetylases metabolism
Lipids toxicity
Liver metabolism
Liver pathology
Sterol Regulatory Element Binding Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 24
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 27866836
- Full Text :
- https://doi.org/10.1016/j.cmet.2016.10.012