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Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression

Lookup NU author(s): Dr Jack LeslieORCiD, Professor Fiona OakleyORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


ObjectiveNon-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the Metabolic Syndrome, linked to increased cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of the adaptive compensatory metabolic programs that modulate non-alcoholic steatohepatitis (NASH) progression is missing.Methods and ResultsTranscriptomics analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of the de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programs was achieved through the activation of Sterol Regulatory Element-Binding Proteins (SREBPs) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP’s in NASH and wound-healing response, we used an Insig1 deficient hyper-efficient SREBP activator murine model. Despite enhanced lipid and cholesterol biosynthesis the Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, the activation of SREBPs resulted in the remodelling of the lipidome, decreased hepatocellular damage, and improved wound-healing responses.ConclusionOur study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for the development of new therapeutic strategies. Moreover, our results suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programs aimed at protecting the liver from lipotoxic insults in NASH.Non-alcoholic fatty liver disease (NAFLD)de novolipogenesis (DNL)lipid remodellingwestern dietcarbon tetracholride (CCl4)liver regeneration

Publication metadata

Author(s): Azzu V, Vacca M, Kamzolas I, Hall Z, Leslie J, Carobbio S, Virtue S, Davies SE, Lukasik A, Dale M, Bohooly-Y M, Acharjee A, Linden D, Bidualt G, Petsalaki E, Griffin Jl, Oakley F, Allison ME, Vidal-Puig A

Publication type: Article

Publication status: Published

Journal: Molecular Metabolism

Year: 2021

Volume: 48

Print publication date: 01/06/2021

Online publication date: 17/03/2021

Acceptance date: 06/03/2021

Date deposited: 09/11/2023

ISSN (electronic): 2212-8778

Publisher: Elsevier BV


DOI: 10.1016/j.molmet.2021.101210

PubMed id: 33722690


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Funder referenceFunder name
C18342/A23390Cancer Research UK CRUK (open competition)
Medical Research Council
MR/R023026/1Medical Research Council (MRC)