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

Kim et al. Cell 175, 133–145, September 20, 2018 (Impact Factor 45.5)

Kim et al. show that while diets rich in glucose lead to insulin-dependent SREBP activation via the SCAP pathway, diets rich in the saturated fatty acids (FAs) and fructose trigger ER stress and INSIG2 induction, which inhibits SCAP-dependent SREBP activation. Instead, ER stress results in Casp2/PIDDosomedependent SREBP activation.

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) andcleaves 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.

Ju Youn Kim,1,9,* Lily Q. Wang,1,8 Valentina C. Sladky,2,8 Tae Gyu Oh,4 Junlai Liu,1 Kaitlyn Trinh,1 Felix Eichin,2 Michael Downes,4 Mojgan Hosseini,5 Etienne D. Jacotot,6,7 Ronald M. Evans,4 Andreas Villunger,2,3 and Michael Karin1,*

1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA, 2 Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria, 3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria, 4 Gene Expression Laboratory, Salk Institute of Biological Studies, La Jolla, CA 9037, USA, 5 Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA, 6 INSERM U1164 Sorbonne Universite´, Campus Pierre et Marie Curie, Paris 75005, France, 7 Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10033, USA, 8 These authors contributed equally, 9 Lead contact