Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression
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-alc...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877821000508 |
| _version_ | 1818360514376368128 |
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| author | Vian Azzu Michele Vacca Ioannis Kamzolas Zoe Hall Jack Leslie Stefania Carobbio Samuel Virtue Susan E. Davies Agnes Lukasik Martin Dale Mohammad Bohlooly-Y Animesh Acharjee Daniel Lindén Guillaume Bidault Evangelia Petsalaki Julian L. Griffin Fiona Oakley Michael E.D. Allison Antonio Vidal-Puig |
| author_facet | Vian Azzu Michele Vacca Ioannis Kamzolas Zoe Hall Jack Leslie Stefania Carobbio Samuel Virtue Susan E. Davies Agnes Lukasik Martin Dale Mohammad Bohlooly-Y Animesh Acharjee Daniel Lindén Guillaume Bidault Evangelia Petsalaki Julian L. Griffin Fiona Oakley Michael E.D. Allison Antonio Vidal-Puig |
| author_sort | Vian Azzu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T21:02:00Z |
| format | Article |
| id | doaj.art-e22a0520a7ea4213a3c9346e79e25390 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-13T21:02:00Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-e22a0520a7ea4213a3c9346e79e253902022-12-21T23:31:34ZengElsevierMolecular Metabolism2212-87782021-06-0148101210Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progressionVian Azzu0Michele Vacca1Ioannis Kamzolas2Zoe Hall3Jack Leslie4Stefania Carobbio5Samuel Virtue6Susan E. Davies7Agnes Lukasik8Martin Dale9Mohammad Bohlooly-Y10Animesh Acharjee11Daniel Lindén12Guillaume Bidault13Evangelia Petsalaki14Julian L. Griffin15Fiona Oakley16Michael E.D. Allison17Antonio Vidal-Puig18Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Liver Unit, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Gastroenterology and Hepatology, Norfolk and Norwich University Hospitals, Norwich, UKWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Bari, ItalyWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UKDepartment of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; Biomolecular Medicine, Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UKNewcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, 5 Newcastle University, Newcastle upon Tyne, UKWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UKWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UKDepartment of Pathology, Cambridge University Hospitals, Cambridge, UKWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UKWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UKTranslational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenDepartment of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, UKBioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, SwedenWellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UKEuropean Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UKDepartment of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; Biomolecular Medicine, Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UKNewcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, 5 Newcastle University, Newcastle upon Tyne, UKLiver Unit, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Corresponding author. The Liver Unit, Cambridge University Hospitals, Box 210, CB2 0QQ, Cambridge, UK.Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK; Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei, Nanjing, China; Corresponding author. TVPlab, MRC Metabolic Diseases Unit, Metabolic Research Laboratories, University of Cambridge, Level 4WT/MRC Institute of Metabolic Science, Box 289, Addenbrooke Hospital, Hills Road, Cambridge, B2 0QQ, UK.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.http://www.sciencedirect.com/science/article/pii/S2212877821000508Non-alcoholic fatty liver disease (NAFLD)De novo lipogenesis (DNL)Lipid remodellingWestern dietCarbon tetrachloride (CCl4)Liver regeneration |
| spellingShingle | Vian Azzu Michele Vacca Ioannis Kamzolas Zoe Hall Jack Leslie Stefania Carobbio Samuel Virtue Susan E. Davies Agnes Lukasik Martin Dale Mohammad Bohlooly-Y Animesh Acharjee Daniel Lindén Guillaume Bidault Evangelia Petsalaki Julian L. Griffin Fiona Oakley Michael E.D. Allison Antonio Vidal-Puig Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression Molecular Metabolism Non-alcoholic fatty liver disease (NAFLD) De novo lipogenesis (DNL) Lipid remodelling Western diet Carbon tetrachloride (CCl4) Liver regeneration |
| title | Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression |
| title_full | Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression |
| title_fullStr | Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression |
| title_full_unstemmed | Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression |
| title_short | Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression |
| title_sort | suppression of insulin induced gene 1 insig1 function promotes hepatic lipid remodelling and restrains nash progression |
| topic | Non-alcoholic fatty liver disease (NAFLD) De novo lipogenesis (DNL) Lipid remodelling Western diet Carbon tetrachloride (CCl4) Liver regeneration |
| url | http://www.sciencedirect.com/science/article/pii/S2212877821000508 |
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