Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature

Abstract

Pregnane X receptor (PXR) is a drug receptor with novel functions in promoting non-alcoholic fatty liver disease (NAFLD). We hypothesize that PXR worsens NAFLD accompanied by gut dysbiosis. Wild-type and PXR-knockout mice were fed control or high fat diet (HFD) for 16-weeks. Serum parameters, liver histopathology, transcriptomic profiling, 16S-rDNA sequencing, and bile acid (BA) metabolomics were performed. PXR enhanced HFD-induced weight gain, hepatic steatosis and inflammation especially in males, accompanied by male-specific and PXR-dependent up-regulation in pro-inflammatory cytokines and microbial response-related genes in liver, an increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, and a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum. The gut dysbiosis was associated with a reduction of hepatic beneficial BAs in males. In conclusion, PXR exacerbates hepatic steatosis and inflammation accompanied by obesity- and inflammation-prone gut microbiome signature, suggesting that gut microbiome may contribute to PXR-mediated exacerbation of NAFLD.

The Function of Xenobiotic Receptors in Metabolic Diseases

“…PXR knockout mice exhibit downregulation of hepatic genes involved in microbial responses and inflammation. This was due to the decrease in pro-inflammatory Lactobacillus and the elevation in anti-inflammatory Bifidobacterium in a PXR-dependent manner in the intestine (Kim S. et al, 2021b).…”

Combinatorial pathway disruption is a powerful approach to delineate metabolic impacts of endocrine disruptors

“…The dietary xenobiotics resulting from PXR-regulated intestinal absorption could impact the physiological function of the liver and adipose tissue and promote steatosis and obesity (among others) [100]. Recently, Kim et al [128] showed the role of PXR in physiopathology of NAFLD, obesity and inflammation linked to gut microbiome dysbiosis using PXRknockout mice. The activation of intestinal PXR is responsible for transcriptional activity of key metabolic enzymes such as the CYP3A4 which is the major expressed P450 in intestinal enterocytes, with levels uncorrelated to those of liver.…”

“…Recently, Kim et al. [128] showed the role of PXR in physiopathology of NAFLD, obesity and inflammation linked to gut microbiome dysbiosis using PXR‐knockout mice. The activation of intestinal PXR is responsible for transcriptional activity of key metabolic enzymes such as the CYP3A4 which is the major expressed P450 in intestinal enterocytes, with levels uncorrelated to those of liver.…”