ArticleLiver international : official journal of the International Association for the Study of the Liver2020
Succinate-GPR-91 receptor signalling is responsible for nonalcoholic steatohepatitis-associated fibrosis: Effects of DHA supplementation.
Article in Liver international : official journal of the International Association for the Study of the Liver, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 59 citations in OpenAlex.
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- Proliferation, migration, and differentiation of circulating ILC precursors in HBV infection-associated fibrosis.European journal of medical research · 2026Article
- Roles of mitochondrial complexes in non-alcoholic fatty liver disease.Frontiers in molecular biosciences · 2026Review
- Macrophages in MASLD: from inflammatory and metabolic crosstalk to exercise intervention.Frontiers in immunology · 2026Review
- Gemigliptin Alleviates Succinate Induced Endoplasmic Reticulum Stress and Activation of Hepatic Stellate Cells.Journal of Korean medical science · 2025Article
- MASH: the nexus of metabolism, inflammation, and fibrosis.The Journal of clinical investigation · 2025Review
- Taurine as a Protective Metabolite in Radiation-Induced Liver Disease: Evidence fromJournal of proteome research · 2025Article
- The peroxisome proliferator-activated receptor α/β/γ agonist NCPC-626 from microbial metabolites alleviates metabolic dysfunction-associated steatohepatitis in mice.Molecular pharmacology · 2025Article
- Silybin inhibits succinate production and secretion in hepatocytes to reverse liver fibrosis.Archives of pharmacal research · 2025Article
- Chronic succinate exposure does not cause liver injury.American journal of physiology. Endocrinology and metabolism · 2025Article
- Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Dimethyl malonate alleviates obstructive nephropathy by enhancing renal metabolism and inhibiting kidney oxidative stress and inflammation.Frontiers in pharmacology · 2025Article
- GPCRs involved in metabolic diseases: pharmacotherapeutic development updates.Acta pharmacologica Sinica · 2024Review
- Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis.Scientific reports · 2024Article
- JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway.Clinical and translational medicine · 2024Article
- Type 2 diabetes and succinate: unmasking an age-old molecule.Diabetologia · 2024Review
- The pathogenic role of succinate-SUCNR1: a critical function that induces renal fibrosis via M2 macrophage.Cell communication and signaling : CCS · 2024Article
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
BACKGROUND AND
aimsTreatment of non-alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH-associated fibrosis in a mouse NASH model and human specimens.
methodsMice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD-HF/G) for 16 weeks; HFCD-HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks.
resultsAlong with NASH progression, fibrotic deposition was documented in HFCD-HF/G-fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase-A (SDH-A) in these mice; whereas, GPR-91 receptor expression was much enhanced in histology compared to control mice, and co-localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid-overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up-regulation of GPR-91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR-91 receptor expression abolished succinate stimulatory role in GPR-91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR-91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens.
conclusionSuccinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR-91 receptor signalling in NASH progression, and the cross-talk between hepatocytes and HSC through GPR-91 signalling is most likely to be the molecular basis of fibrogenesis in NASH.
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