Hepatocyte specific deletion of HIF‐1α affects gut microbiota composition in HFD fed mice

Abstract

Hepatic hypoxia inducible factor‐1α (HIF‐1α) is a mediator of chronic liver diseases including alcoholic and nonalcoholic fatty liver disease in mice. Our previous study has shown that HIF‐1α signaling pathway is engaged in exercise‐induced protection against cholestasis. Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota. High‐fat diet (HFD) feeding causes intestinal hyperpermeability and microbial dysbiosis. Therefore, we hypothesized that hepatic HIF‐1α is engaged in the bile acid metabolism and intestinal innate immunity in response to HFD feeding. Albumin Cre mediated, hepatocyte specific deletion of Hif1a (Hif1aLKO) mice were generated. Hepatic metabolism related genes expression patterns were different between the control (Hif1afl/fl) and Hif1aLKO mice. Next, we fed Hif1aLKO and Hif1afl/fl mice (male, 6‐week, n=6 per group) with normal or high‐fat diet (60% fat) for 8‐week. The accumulation of lipid in liver was detected by microCT and Oil Red O staining. Bile acid profile was analyzed by high performance liquid chromatography. The body weight, liver weight, fasting plasma glucose (FPG), serum biomarkers related to liver function and lipid metabolism were also evaluated. Expression levels of bile acid metabolism and intestinal antimicrobial responses related genes were determined using PCR array. Feces were collected on the 0th, 3th and 8th week of HFD feeding. The fecal microbial DNA was extracted and sequenced on an Illumina MiSeq platform. After HFD challenge, Hif1aLKO mice developed greater levels of fat in liver and enhanced FPG (8.5±0.8 vs. 6.1±0.5 mmol/L, P<0.05). Hepatocyte HIF‐1α deletion increased expression of genes involved in bile acid synthesis and affected bile acid profile in liver. HFD‐fed Hif1aLKO mice also exhibited severer intestinal inflammation compare with Hif1afl/fl, and alterations of intestinal gene profile related to antimicrobial responses. Community richness of Hif1aLKO gut microbiome was lower than that of Hif1afl/fl before HFD feeding (ACE index: 328.5±36.6 vs. 403.1±22.3, P<0.05; and Chao1 index: 336.0±34.9 vs. 414.5±26.8, P<0.05). In Figure 1, principal coordinates analysis (PCoA) based on unweighted Unifrac distances highlighted a clear clustering of the microbial populations of Hif1aLKO away from that of Hif1afl/fl. The relative abundances of the given genus within each sample were presented in Heatmap (Figure 2). Notably, there were significantly lower proportions of Akkermansia, Alloprevotella, Allobaculum and Prevotella in Hif1aLKO mice as compared to Hif1afl/fl. Taken together, these results demonstrated that hepatic HIF‐1α is involved in HFD feeding induced changes in gut microbiota composition.Support or Funding InformationPeijie Chen: National Natural Science Foundation of China (31471135). Beibei Luo: National Natural Science Foundation of China (31701040), China Postdoctoral Science Foundation (2015M572679), Shanghai Sailing Program (17YF1418000) and Chenguang Program (16CG57).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.