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ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P.

Citation
Kim, J. Y., et al. “Er Stress Drives Lipogenesis And Steatohepatitis Via Caspase-2 Activation Of S1P.”. Cell, pp. 133-145.e15.
Center UCSD-UCLA
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Author Ju Youn Kim, Ricard Garcia-Carbonell, Shinichiro Yamachika, Peng Zhao, Debanjan Dhar, Rohit Loomba, Randal J Kaufman, Alan R Saltiel, Michael Karin
Keywords DNL, NASH, SREBP, caspase-2, Hepatic Steatosis, lipogenesis, liver fibrosis, site 1 protease
Abstract

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.

Year of Publication
2018
Journal
Cell
Volume
175
Issue
1
Number of Pages
133-145.e15
Date Published
12/2018
ISSN Number
1097-4172
DOI
10.1016/j.cell.2018.08.020
Alternate Journal
Cell
PMID
30220454
PMCID
PMC6159928
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