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Intestinal epithelial cell‐specific deletion of Hif1a affects the hepatic energy metabolism in cholestasis induced liver injury
Author(s) -
Luo Beibei,
Xiang Dao,
Cao Wei,
Huang Xiaoqian,
Wu Die,
Chen Peijie
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07484
Subject(s) - hif1a , cholestasis , bile acid , chemistry , metabolism , medicine , biology , hypoxia (environmental) , in vivo , endocrinology , biochemistry , oxygen , organic chemistry , microbiology and biotechnology , gene
The hypoxia‐inducible factor (HIF) and its prolyl hydroxylases (PHDs) are pivotal in the transcriptional response to oxygen flux. Our previous study found that exercise elevates in vivo HIF‐1α expression in the small intestine and liver. Hepatic HIF‐1α and PHD2 signaling pathways are involved in exercise‐induced protection against cholestasis. Bile acids are synthesized from cholesterol and further metabolized by the intestinal microbiota. The integrity of intestinal barrier and the function intestinal epithelial cell (IEC) are regulated by HIF‐1α. Therefore, we hypothesized that intestinal HIF‐1α and PHD2 are engaged in the hepatic energy metabolism in response to cholestasis. The noninvasive bioluminescence imaging was applied to monitor HIF‐1α expression in ROSA26 ODD‐Luc /+ mouse model (ODD‐Luc) that ubiquitously expresses a bioluminescent reporter consisting of firefly luciferase fused to a region of HIF‐1α. We found that in vivo HIF‐1α markedly increases in the small intestine of DDC fed ODD‐Luc mice. Next, the Villin Cre mediated, IEC‐specific deletion of Hif1a (Hif1a VKO ) and IEC‐specific deletion of Phd2 (Phd2 VKO ) mice were generated. We fed Hif1a VKO , Phd2 VKO and wild‐type (Hif1a fl/fl and Phd2 fl/fl ) mice (male, 8‐week, n=6–8 per group) with normal chow or 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine (DDC) for 4 weeks, to induce cholestasis with biliary obstruction and bile duct injury. The liver structure was detected by H&E staining. Bile acid profile was analyzed by high performance liquid chromatography. Expression levels of bile acid metabolism related genes were determined using PCR array. The body weight, liver weight, albumin, alanine aminotransferase, aspartate aminotransferase, total bilirubin, triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol levels were also measured. All animal experiments were performed in compliance with and approved by the university ethical review board. The data was shown that DDC fed mice were suffered from cholestasis including biliary obstruction and bile duct injury with no group differences. The cholestasis induced symptoms in body weight reduction and liver injury related makers in DDC‐Hif1a VKO were severer. In Hif1a VKO , bile acid synthesisgenes related genes expression were increased. IEC Hif1a deletion affected bile acid profile in liver. The levels of taurocholic acid sodium salt hydrate, glycocholic acid hydrate synthetic and taurodeoxycholic acid sodium salt monohydrate were higher in Hif1a VKO (p<0.05), compared to Hif1a fl/fl . Taken together, these results demonstrated that intestinal HIF‐1α signaling is involved in the hepatic energy metabolism in cholestasis induced liver injury. Support or Funding Information The National Natural Science Foundation of China (31701040, 31801003 and 31471135), Shanghai Sailing Program (17YF1418000) and Chenguang Program (16CG57).