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Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression
- Source :
- Molecular Metabolism, Vol 48, Iss, Pp 101210-(2021), Molecular Metabolism
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Objective Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and results Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Conclusions Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.<br />Highlights • Human NASH biopsies’ transcriptomics analysis features metabolic pathway rewiring. • SCAP/SREBP/INSIG1 modulation promotes lipid/cholesterol synthesis/remodelling in NASH. • Loss of Insig1 promotes lipid remodelling, preventing hepatic lipotoxicity in NASH. • Loss of Insig1 improves liver damage and wound healing and restrains NASH progression.
- Subjects :
- Liver Cirrhosis
Male
0301 basic medicine
medicine.medical_treatment
0601 Biochemistry and Cell Biology
Mice
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
Medicine
Western diet
Carbon tetrachloride (CCl(4))
Internal medicine
Lipid remodelling
Mice, Knockout
Fatty liver
De novo lipogenesis (DNL)
Intracellular Signaling Peptides and Proteins
Middle Aged
Liver regeneration
Cholesterol
Lipotoxicity
Disease Progression
Female
lipids (amino acids, peptides, and proteins)
Carbon tetrachloride (CCl4)
030209 endocrinology & metabolism
Brief Communication
digestive system
Non-alcoholic fatty liver disease (NAFLD)
03 medical and health sciences
Downregulation and upregulation
Animals
Humans
Molecular Biology
business.industry
Lipogenesis
Insulin
Membrane Proteins
Cell Biology
0606 Physiology
medicine.disease
RC31-1245
digestive system diseases
Sterol regulatory element-binding protein
Mice, Inbred C57BL
030104 developmental biology
Diet, Western
Cancer research
Insulin Resistance
Steatohepatitis
Metabolic syndrome
Transcriptome
business
Biomarkers
Subjects
Details
- ISSN :
- 22128778
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Molecular Metabolism
- Accession number :
- edsair.doi.dedup.....e2955875d5f80b3ec4b5ad3aa4e50cf0