Pregnane X receptor (PXR) deficiency improves high fat diet-induced obesity via induction of fibroblast growth factor 15 (FGF15) expression
| Autor: | Jia-Yi Xu, Shu-Yun Zhang, Zhe Shi, Neal A. Englert, Li-Yang Zhao |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Receptors Steroid medicine.medical_specialty medicine.drug_class Gene Expression Receptors Cytoplasmic and Nuclear Biology Diet High-Fat Kidney Cholesterol 7 alpha-hydroxylase digestive system Biochemistry Bile Acids and Salts Feces 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Constitutive androstane receptor medicine Animals Obesity Constitutive Androstane Receptor Triglycerides Mice Knockout Pharmacology Pregnane X receptor Triglyceride Bile acid FGF15 Body Weight Pregnane X Receptor Organ Size Fibroblast Growth Factors Mice Inbred C57BL 030104 developmental biology Endocrinology Liver chemistry Nuclear receptor 030220 oncology & carcinogenesis CYP8B1 |
| Zdroj: | Biochemical Pharmacology. 142:194-203 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2017.07.019 |
| Popis: | Obesity has become a significant global health problem, and is a high risk factor for a variety of metabolic diseases. Fibroblast growth factor (FGF) 15 plays an important role in the regulation of metabolism. Xenobiotic-sensing nuclear receptors pregnane X receptor (PXR/NR1I2) and constitutive androstane receptor (CAR/NR1I3) play important roles in xenobiotic detoxification and metabolism, and also are involved in the regulation of energy metabolism. However, the effects that PXR and CAR have on the regulation of FGF15 are unknown. Here, we found that body weight, hepatic triglyceride levels, liver steatosis, and hepatic mRNA expression levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1), the key enzymes in the bile acid classical synthesis pathway, were significantly decreased in high fat diet (HFD)-fed PXR knockout (KO) mice compared to HFD-fed wild-type mice. Interestingly, intestinal FGF15 expression levels were significantly elevated in HFD-fed PXR KO mice compared with HFD-fed wild-type mice. Additionally, serum total bile acid levels were significantly decreased in PXR KO mice than those in wild-type mice when fed a control diet or HFD. Total lipids in feces were significantly increased in HFD-fed PXR KO mice compared to HFD-fed wild-type mice. However, these alterations were not found in HFD-fed CAR KO mice. These results indicate that PXR deficiency improves HFD-induced obesity via induction of FGF15 expression, resulting in suppression of bile acid synthesis and reduction of lipid absorption, hepatic lipid accumulation and liver triglyceride levels. Our findings suggest that PXR may negatively regulate FGF15 expression and represent a potential therapeutic target for the treatment for metabolic disorders such as obesity. |
| Databáze: | OpenAIRE |
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