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ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P
Open accessAbstract
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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“Thus, ER stress might contribute to the development of increased hepatic DNL in hepatic IR, at least in the advanced stages of MASLD/MASH [91].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [91]
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“A study showed that ER-stress-mediated SREBP1/2 activation, TG and cholesterol accumulation, as well as MASH progression, all depend on Casp2 [91].”
From Hepatic Insulin Resistance and Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Insights into Mechanisms and Clinical Implications (2025) · cites this paper as [91]
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Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 175
- Issue
- 1
- Pages
- 133-145.e15
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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