ArticleCell metabolism2022
PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis.
Article in Cell metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 34 citations in OpenAlex.
- S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via noncanonical SREBP2 signaling.The Journal of clinical investigation · 2026Article
- Comparative insights into the apoptosome, inflammasomes and PIDDosome.Nature reviews. Immunology · 2026Review
- [Mesenchymal stem cell-derived exosomes: a new hope for metabolic-associated fatty liver disease].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2026Review
- The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development.Cell death and differentiation · 2026Article
- PARP4 ADP-ribosylates PIDD1 to complete a phospho/SUMO/PAR-ylation cascade that orchestrates PIDDosome assembly.Science advances · 2026Article
- Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
- Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice.Science advances · 2026Article
- Differential effects of fresh and black garlic extracts on oxidative stress regulation and anti-inflammatory response properties in human HepG2 cells: AnFrontiers in pharmacology · 2026Article
- Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.Pharmacological reviews · 2025Review
- Genomic medicine in hepatology: mechanisms and liver treatment strategies.Molecular medicine (Cambridge, Mass.) · 2025Review
- Recent Progress of Sterol Regulatory Element-binding Proteins Role in Atherosclerosis.Current atherosclerosis reports · 2025Review
- Lipogenesis and MASLD: re-thinking the role of SREBPs.Archives of toxicology · 2025Review
- MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives.Molecular oncology · 2025Review
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
- Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.International journal of molecular sciences · 2024Review
- Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective.Metabolites · 2024Review
- Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis.Metabolism open · 2024Review
- Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.Acta pharmacologica Sinica · 2024Article
- Genome-wide loss-of-function genetic screen identifies INSIG2 as the vulnerability of hepatitis B virus-integrated hepatoma cells.Cancer science · 2024Article
- A cholesterol-binding bacterial toxin provides a strategy for identifying a specific Scap inhibitor that blocks lipid synthesis in animal cells.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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13 authors at 5 institutions in 3 countries.
Funding
Abstract
Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.