Cited by 333Liver Disease Diagnosis and TreatmentEndoplasmic Reticulum Stress and DiseaseCancer, Lipids, and Metabolism

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

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Kim, Ju Youn, Garcia-Carbonell, Ricard, Yamachika, Shinichiro, Zhao, Peng, Dhar, Debanjan, Loomba, Rohit, Kaufman, Randal J., Saltiel, Alan R., Karin, Michael·2018·Cell

DOI 10.1016/j.cell.2018.08.020PMC PMC6159928

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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.

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Authors: Kim, J. Y., Garcia-Carbonell, R., Yamachika, S., Zhao, P., Dhar, D., Loomba, R., Kaufman, R. J., Saltiel, A. R., & Karin, M.
Affiliations: University of California San Diego (US)
Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author: Karin, Michael
ORCID: Kim, Ju Youn
Yamachika, Shinichiro
Zhao, Peng
Dhar, Debanjan
Loomba, Rohit
Kaufman, Randal J.
Saltiel, Alan R.
Karin, Michael
Venue: Cell
Publisher: Elsevier BV
Published: 2018-09
Volume: 175
Issue: 1
Pages: 133-145.e15
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2018.08.020
PMC: PMC6159928
OpenAlex: W2890819762
Cited by: 333
References: 59
Citations by year: 2026: 16 · 2025: 45 · 2024: 48 · 2023: 49 · 2022: 49 · 2021: 49 · 2020: 49 · 2019: 24 · 2018: 4
FWCI: 24.60
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: NIH
NCI (R01CA211794, R01CA198103, R01CA155120)
NIEHS (P42ES010337)
NHMRC (APP112227)
AACR-Bayer Hepatocellular Carcinoma Fellowship (16-40-44-KIMJ)
Diabetes Research Center Pilot and Feasibility Grant (P30DK063491)
Boehringer Ingelheim Fonds
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords: endoplasmic reticulum stress, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, caspase-2, site-1 protease, de novo lipogenesis, hepatic steatosis, free cholesterol accumulation, triglyceride accumulation
MeSH terms: Animals, Cholesterol, Endoplasmic Reticulum, Fatty Liver, Humans, Liver, Mice, Inbred C57BL, Serine Endopeptidases, Triglycerides, Hepatocytes, Proprotein Convertases, Lipogenesis, Mice, Sterol Regulatory Element Binding Protein 1, Caspase 2, HEK293 Cells, Endoplasmic Reticulum Stress

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

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