Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice

Abstract

Obesity is a complex metabolic disorder that is more prevalent among women. Until now, the only relevant rodent models of diet-induced obesity were via the use of ovariectomized (“postmenopausal”) females. However, recent reports suggest that the xenobiotic nuclear receptor pregnane X receptor (PXR) may contribute to obesity. Therefore, we compared the roles of mouse and human PXRs in diet-induced obesity between wild type (WT) and PXR-humanized (hPXR) transgenic female mice fed either control or high-fat diets (HFD) for 16 weeks. HFD-fed hPXR mice gained weight more rapidly than controls, exhibited hyperinsulinemia, and impaired glucose tolerance. Fundamental differences were observed between control-fed hPXR and WT females: hPXR mice possessed reduced estrogen receptor α (ERα) but enhanced uncoupling protein 1 (UCP1) protein expression in white adipose tissue (WAT); increased protein expression of the hepatic cytochrome P450 3A11 (CYP3A11) and key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, and increased total cholesterol. Interestingly, HFD ingestion induced both UCP1 and glucokinase protein expression in WT mice, but inhibited these enzymes in hPXR females. Unlike WT mice, CYP3A11 protein, serum 17β-estradiol levels, and WAT ERα expression were unaffected by HFD in hPXR females. Together, these studies indicate that the hPXR gene promotes obesity and metabolic syndrome by dysregulating lipid and glucose homeostasis while inhibiting UCP1 expression. Furthermore, our studies indicate that the human PXR suppresses the protective role of estrogen in metabolic disorders. Finally, these data identify PXR-humanized mice as a promising in vivo research model for studying obesity and diabetes in women.

Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

“…However, CAR and PXR appear to have opposite effects on metabolic disease. We and others have reported that activation of PXR promoted hepatic steatosis and insulin resistance (21,(27)(28)(29). PXR transgenic mice showed hyperlipidemia, fatty liver and impaired glucose and insulin tolerance (21,(27)(28)(29).…”

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

“…In fact, it is becoming clear that nutrient excess conditions promote global hepatic acetylation of metabolic regulators in general, including NRs, for metabolic adaptation [87–93]. A counter argument is that this acetylation state/level could simply reflect an adaptation to increased expression of PXR in HFD- fed rodents [86, 94, 95]. …”

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

“…For comparison, we examined the expression of the predominant mouse hepatic Cyp3a11 enzyme in the SS model and found a trend toward lower (20% 6 6%, P = 0.10) mRNA expression levels in mice on a high-fat diet (n = 6) than in those on a normal diet (n = 6). In the context of previous reports, results in mouse models of NAFLD have been heterogeneous with some demonstrating decreased (Yoshinari et al, 2006;Ghose et al, 2011;Wahlang et al, 2014) or induced (Fisher et al, 2008;Spruiell et al, 2014) expression of Cyp3a11. Similarly, rat models of hepatic steatosis are conflicting, with some reporting decreased Cyp3a expression (Leclercq et al, 1998) and others showing higher levels (Ghoneim et al, 2015).…”