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. PPARα 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 PPARα 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). PPARα levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPARα 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 PPARα is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation via the gut-liver axis.

AIM: To observe the effect of piceatannol on the kidney of diabetic nephropathy rats in early stage, and to explore the possible mechanisms.METHODS: The rats were randomly divided into 5 groups: control group, model group, low dose of piceatannol treatment group, medium dose of piceatannol treatment group and high dose of piceatannol treatment group.The rat model of diabetic nephropathy was induced accordingly, and the rats received 20 mg/kg, 40 mg/kg or 60 mg/kg of piceatannol by gavage once a day for 4 weeks.Blood glucose was detected by glucometer.The urea nitrogen and creatinine levels in the serum were measured by urease-glutamate dehydrogenase enzymatic and inosine acid oxidase methods, respectively, and 24 h urinary microalbumin was analyzed by immune transmission turbidimetry test.Moreover, the pathological changes of the kidney tissues were observed under microscope with HE staining.The protein expression of TGF-β1 and Smad 7 and the phosphorylation levels of Smad2 and Smad3 were determined by Western blot.RESULTS: Compared with model group, piceatannol treatment significantly decreased the levels of blood glucose, blood urea nitrogen and urinary microalbumin, but had no effects on serum creatinine.Furthermore, HE staining showed that the increased mesangial cells, matrix hyperplasia and degenerated epithelial cells in model group were markedly inhibited after piceatannol treatment.Additionally, piceatannol treatment also reduced the protein expression of TGF-β1 and Smad 7, and the phosphorylation levels of Smad2 and Smad3.CONCLUSION: Piceatannol attenuates pathological progression in the kidney of diabetic nephropathy rats in early stage, which may be through inhibiting TGF-β/Smad signaling pathway.