TitlePhysiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP.
Publication TypeJournal Article
Year of Publication2016
AuthorsPapazyan, R, Sun, Z, Kim, YHoon, Titchenell, PM, Hill, DA, Lu, W, Damle, M, Wan, M, Zhang, Y, Briggs, ER, Rabinowitz, JD, Lazar, MA
JournalCell Metab
Date Published2016 Dec 13
KeywordsAnimals, Base Sequence, Fatty Acids, Fatty Liver, Glucose, Histone Deacetylases, Inflammation, Lipids, Lipogenesis, Liver, Mice, Inbred C57BL, Mice, Knockout, Oxidation-Reduction, Oxidative Stress, Protein Binding, Sterol Regulatory Element Binding Protein 1, Transcription, Genetic, Triglycerides

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.

Alternate JournalCell Metab.
PubMed ID27866836
PubMed Central IDPMC5159233
Grant ListP30 DK050306 / DK / NIDDK NIH HHS / United States
F32 DK108555 / DK / NIDDK NIH HHS / United States
T32 GM008216 / GM / NIGMS NIH HHS / United States
F32 DK101175 / DK / NIDDK NIH HHS / United States
R00 DK099443 / DK / NIDDK NIH HHS / United States
R37 DK043806 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States