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

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