Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.

良性肝脂肪变性受脂质摄取、从头脂肪生成和脂肪酸 (FA) 氧化的影响，在压力和炎症下进展为非酒精性脂肪性肝炎 (NASH)。建议增加肝脂肪变性和 NASH 风险的关键常量营养素是果糖。过量摄入果糖会导致肠道屏障恶化和内毒素血症。然而，果糖如何触发这些改变及其在脂肪肝和 NASH 发病机制中的作用仍然未知。在这里，我们使用小鼠展示了微生物群衍生的 Toll 样受体 (TLR) 激动剂促进肝脂肪变性而不影响 1-磷酸果糖 (F1P) 和细胞溶质乙酰辅酶 A。激活粘膜再生 gp130 信号，YAP 诱导的基质细胞蛋白 CCN1 的给药或抗菌肽 Reg3b（β）肽的表达抵消了果糖诱导的屏障退化，这取决于内质网应激和随后的内毒素血症。内毒素与 TLR4 结合以触发肝脏巨噬细胞产生 TNF，从而诱导脂肪生成酶，将小鼠和人类肝细胞中的 F1P 和乙酰辅酶 A 转化为 FA。