ArticleThe Journal of clinical investigation2022
Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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71 citing papers in PubMed, 101 citations in OpenAlex.
- Cholesterol-responsive NFE2L1-INSIG1 interaction controls VLDL secretion and metabolic dysfunction-associated steatohepatitis pathogenesis in mice.The Journal of clinical investigation · 2026Article
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- TP53-META, a meta-analysis tool for comparative transcriptomics of TP53 dependency: examples from target silencing and liver fibrosis.BMC bioinformatics · 2026Article
- Role of SCAP in regulation of pancreatic homeostasis, pancreatitis, and tumorigenesis.Oncogene · 2026Article
- Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
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- The Role of Crosstalk Between the Unfolded Protein Response and Autophagy in Diseases Associated with Sympathetic Nervous System Imbalance: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Microarray Data Analysis of Gene Crosstalk Between Psoriasis and Non-Alcoholic Fatty Liver Disease.Clinical, cosmetic and investigational dermatology · 2026Article
- Metabolic reprogramming in cardiac fibrosis: mechanisms, crosstalk, and therapeutic interventions.Frontiers in physiology · 2026Review
- Review
- Hepatocyte SAMHD1 Deficiency Attenuates Hepatic Steatosis via Suppression of SREBP Activation in a Mouse Model of Metabolic-Associated Steatotic Liver Disease.International journal of biological sciences · 2026Article
- Etiology-Driven Mouse Models of Hepatocellular Carcinoma: Paving the Way for Precision Oncology.Journal of hepatocellular carcinoma · 2026Review
- VB-84922 is a small molecule that inhibits ER-to-golgi transport of SREBPs-SCAP complexes.Frontiers in pharmacology · 2026Article
- Lipid metabolism-MAFLD crosstalk: mechanisms and therapy.Frontiers in endocrinology · 2026Review
- Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review).International journal of molecular medicine · 2025Review
- A Novel Sesquiterpene fromMolecules (Basel, Switzerland) · 2025Article
- Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.Pharmacological reviews · 2025Review
- Ferroptosis: biology and role in liver disease.Journal of gastroenterology · 2025Review
- Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications.World journal of hepatology · 2025Review
11 more citing papers are in PubMed but not listed here.
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26 authors at 8 institutions in 2 countries.
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Abstract
Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.
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