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.

Objective To investigate the analgesic efficacy,quality of life,and the incidence of adverse reactions of palliative radiotherapy combined with the principle of three-step analgesic ladder in treatment of metastatic bone pain in non-small cell lung cancer (NSCLC).Methods A total of 88 NSCLC patients with metastatic bone pain at Fujian Provincial Hospital from April 2015 to April 2018 were retrospectively analyzed.According to the treatment,the patients were divided into the combined group and the control group,and 44 cases in each group.The combined group was given palliative radiotherapy combined with the principle of three-step analgesic ladder,and the control group received the principle of three-step analgesic ladder.The analgesic efficacy,changes of quality of life,and the incidence of adverse reactions were compared between the two groups.Results The total analgesic effective rate in the combined group was higher than that in the control group [84.1％ (37/44) vs.54.5 ％ (24/44)],and the difference between the two groups was statistically significant (Z =-3.227,P =0.001).For mild and moderate pain,the effective rate in the combined group and control group were 84.6 ％ (11/13) vs.57.1％ (8/14),80.0 ％ (12/15) vs.42.9 ％ (6/14) respectively,and the differences were not statistically significant (Z =-1.473,P =0.141;Z =-1.793,P =0.073).For severe pain,the effective rates in the combined group and control group were 87.5 ％ (14/16) and 62.5 ％ (10/16),and the difference was statistically significant (Z =-2.327,P =0.020).The quality of life in the combined group was better than that in the control group,and the difference between the two groups was statistically significant (Z =-2.254,P =0.024).The overall incidence rate of adverse reactions in the combined group was 36.4 ％ (16/44),which was significantly lower than that in the control group [59.1％ (26/44)],and the difference between the two groups was statistically significant (x2 =4.55,P =0.033).Conclusion Palliative radiotherapy combined with the principle of three-step analgesic ladder in treatment of metastatic bone pain of NSCLC can significantly improve the efficacy,especially for severe pain,and improve the quality of life,and reduce the incidence of adverse reactions.