Deficiency in Gpr43 lead to exacerbation of NAFLD/NASH symptoms

Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. We found that the consumption of a prebiotic, inulin, markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome and increased the concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Furthermore, the absence of G-protein-coupled receptor 43 (GPR43), an acetate receptor, abolished the protective effect of inulin, indicated by more sever liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. These findings demonstrate that the commensal microbiome-acetate-GPR43 axis improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH.

非酒精性脂肪性肝病（Non-alcoholic liver disease, NAFLD）是代谢综合征的肝脏表型，可进展为非酒精性脂肪性肝炎（Non-alcoholic steatohepatitis, NASH）。肠道微生物组的异常改变与NAFLD/NASH的发生发展密切相关，但其潜在机制仍未明确。本研究发现，摄入益生元菊粉（inulin）可显著改善小鼠体内NAFLD/NASH的表型，包括肝脂肪变与肝纤维化。菊粉摄入可引发肠道微生物组的整体重塑，并提升肠腔与门静脉血中的短链脂肪酸浓度，其中尤以乙酸的升高最为显著。摄入产乙酸抗性淀粉同样可预防NAFLD的发生发展。进一步研究表明，缺失乙酸受体G蛋白偶联受体43（G-protein-coupled receptor 43, GPR43）会完全取消菊粉的保护作用，表现为更严重的肝肥大、高胆固醇血症与炎症反应，该效应可归因于肝脏而非肌肉或脂肪组织的胰岛素抵抗加剧。本研究结果证实，共生微生物组-乙酸-GPR43轴可改善肝脏胰岛素敏感性，从而阻断NAFLD/NASH的发生发展。