Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature
| Autor: | Moumita Dutta, Sora Choi, Jeffrey O. Asubonteng, Julia Yue Cui, Frank J. Gonzalez, Maxwell A. Gyamfi, Sarah Kim, Marianne Polunas, Michael Goedken |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Inflammation Gut flora Chronic liver disease Diet High-Fat digestive system Biochemistry Article Mice Sex Factors Ruminococcus gnavus Non-alcoholic Fatty Liver Disease Internal medicine RNA Ribosomal 16S Nonalcoholic fatty liver disease medicine Animals Gene Regulatory Networks Obesity Pharmacology Mice Knockout Pregnane X receptor Bile acid biology business.industry Pregnane X Receptor Glucose Tolerance Test medicine.disease biology.organism_classification digestive system diseases Gastrointestinal Microbiome Mice Inbred C57BL RNA Bacterial Endocrinology Liver Female medicine.symptom Steatosis business Biomarkers |
| Zdroj: | Biochem Pharmacol |
| ISSN: | 1873-2968 |
| Popis: | Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease due to the current epidemics of obesity and diabetes. The pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor known for trans-activating liver genes involved in drug metabolism and transport, and more recently implicated in energy metabolism. The gut microbiota can modulate the host xenobiotic biotransformation and contribute to the development of obesity. While the male sex confers a higher risk for NAFLD than women before menopause, the mechanism remains unknown. We hypothesized that the presence of PXR promotes obesity by modifying the gut-liver axis in a sex-specific manner. Male and female C57BL/6 (wild-type/WT) and PXR-knockout (PXR-KO) 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 PXR-dependent up-regulation in hepatic genes involved in microbial response, inflammation, oxidative stress, and cancer; PXR-dependent increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, as well as a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum, with a PXR-dependent reduction of beneficial BAs in liver. The resistance to NAFLD in females may be explained by PXR-dependent decrease in pro-inflammatory bacteria (Ruminococcus gnavus and Peptococcaceae). 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. |
| Databáze: | OpenAIRE |
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