Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP

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 cr...

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Veröffentlicht in:Cell metabolism 2016-12, Vol.24 (6), p.863-874
Hauptverfasser: Papazyan, Romeo, Sun, Zheng, Kim, Yong Hoon, Titchenell, Paul M., Hill, David A., Lu, Wenyun, Damle, Manashree, Wan, Min, Zhang, Yuxiang, Briggs, Erika R., Rabinowitz, Joshua D., Lazar, Mitchell A.
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •HDAC3 and SCAP/SREBP1 control distinct pathways of lipid metabolism in the liver•Their depletion paralyzes liver lipid metabolism, leading to lipotoxicity and NASH•Lipotoxicity is prevented by activation of lipogenesis and triglyceride synthesis•Lipid storage as triglyceride can be beneficial in liver inflammation and injury Papazyan et al. show complementary crosstalk between the lipid metabolism pathways HDAC3 and SCAP/SREBP1c. When both pathways are compromised, toxic accumulation of lipid intermediates in the liver precipitates an aggressively lethal form of non-alcoholic steatohepatitis, which can be prevented by augmenting de novo lipogenesis and triglyceride synthesis to ameliorate lipotoxicity.
ISSN:1550-4131
1932-7420
1932-7420
DOI:10.1016/j.cmet.2016.10.012