PPARα affects hepatic lipid homeostasis by perturbing necroptosis signals in the intestinal epithelium

作者：Shufang Na, Yanjie Fan, Honglei Chen, Ling Li, Guolin Li, Furong Zhang, Rong-Yan Wang, Yafei Yang, Zixia Shen, Zhuang Peng, Yafei Wu, Yong Zhu, Zheqiong Yang, Guicheng Dong, Qifa Ye, Jiang Yue · 发表于：Acta Pharmaceutica Sinica B · 年份：2024 · DOI：10.1016/j.apsb.2024.08.021 · 被引用次数：10 · 研究领域：Liver Disease Diagnosis and Treatment、Peroxisome Proliferator-Activated Receptors、Metabolism and Genetic Disorders

Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutrients and defend against environmental insults, whereas inappropriate death promotes the spread of inflammation. PPAR α is highly expressed in the small intestine and regulates the absorption of dietary lipids. However, as a key mediator of inflammation, the impact of intestinal PPAR α signaling on cell death pathways is unknown. Here, we show that Pparα deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal Pparα deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPAR α levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPAR α up-regulates necroptosis signals in the intestinal organoids triggered by TNF- α and LPS stimuli via TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal Pparα deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPAR α is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation via the gut–liver axis. Pparα deficiency in the ileum epithelium up-regulates necroptosis signals via TRIM38/TRIF and CREB3L3/MLKL pathways, leading to hepatic steatosis through the spread of gut-derived endotoxin.