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

Abstract

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 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 signaling on cell death pathways is unknown. Here, we show that deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPAR levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPAR up-regulates necroptosis signals in the intestinal organoids triggered by TNF- and LPS stimuli TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPAR is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation the gut–liver axis.