PPARα affects hepatic lipid homeostasis by perturbing necroptosis signals in the intestinal epithelium.
10.1016/j.apsb.2024.08.021
- Author:
Shufang NA
1
;
Yanjie FAN
1
;
HongLei CHEN
2
;
Ling LI
3
;
Guolin LI
4
;
Furong ZHANG
1
;
Rongyan WANG
1
;
Yafei YANG
1
;
Zixia SHEN
1
;
Zhuang PENG
1
;
Yafei WU
1
;
Yong ZHU
1
;
Zheqiong YANG
1
;
Guicheng DONG
5
;
Qifa YE
3
;
Jiang YUE
1
Author Information
1. Department of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
2. Department of Pathology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
3. Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Provincial Clinical Research Center for Natural Polymer Biological Liver, Wuhan 430071, China.
4. Center for Biomedical Aging, National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China.
5. College of Life Science, Inner Mongolia Agricultural University, Hohhot 010011, China.
- Publication Type:Journal Article
- Keywords:
Butyric acid;
Gut–liver axis;
Intestine;
LPS;
Liver;
NAFLD;
Necroptosis;
PPARα
- From:
Acta Pharmaceutica Sinica B
2024;14(11):4858-4873
- CountryChina
- Language:English
-
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. 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.
