# The Nuclear Receptor PXR in Chronic Liver Disease
## 7 PXR-Related Gender Differences in Chronic Liver Disease  
A marked gender difference characterizes chronic liver diseases since males are more prone to develop NAFLD/NASH, fibrosis, and HCC with respect to females [107]. Accordingly, sex-related dimorphisms of hepatic PXR have been postulated and investigated in many studies. [PERSON] and colleagues demonstrated that PXR has a female-specific inhibitory activity on the transcription of hepatic genes involved in immune functions such as cytokine secretion and leukocyte recruitment [107]. Interestingly, the genetic deletion of PXR downregulates the transcription of these genes more severely in female than male mice. Although the mechanisms underlying this effect remain essentially unknown, it has been demonstrated that the activation of PXR could interfere with the homeostasis of sex hormones by increasing the catabolism of androgen and estrogens operated by CYPs and sulfotransferases. Thus, it has been hypothesized that PXR concurs in maintaining steroid hormone balance, sexual maturation, and hepatic immune function in females. The loss of PXR induced a significant downregulation of hepatic sex-specific genes regulating osteoclast differentiation, T cell activation, phagocytosis, and inflammatory responses [107]. In addition, it has been demonstrated that PXR activation might impact the metabolism of glucose and lipids, as well as xenobiotic detoxification, in a gender-related manner [107]. Hence, PXR-humanized (hPXR) transgenic mice allowed the observation that PXR played a gender-dependent role in ethanol-induced liver damage. Indeed, although the level of alcohol dehydrogenase (ADH) was comparable in female and male mice, females were less affected by ethanol-induced acute injury than males [108]. Accordingly, further analysis evaluating CYP2E1 and lactoperoxidase (LPO) levels, which are the source and the main marker of oxidative stress, respectively, revealed that the amount of oxidative stress was higher in males [108]. In the same model, gender-related differences have also been demonstrated in lipid metabolism since females showed an increased mRNA expression of genes involved in the uptake of fatty acids, in the catabolism of lipids, and in the formation of very low-density lipoproteins (VLDL) (_L-fabp-1_ and _Mttp_). On the other hand, male mice had a greater susceptibility to the development of steatosis with respect to females, where an inhibition of the pro-steatotic _Pemt_ gene was observed [108]. Moreover, gender-related multiple gene variants or post-translational modifications of PXR structure have been reported in many liver diseases and might be considered as risk factors. For example, it has been demonstrated that single nucleotide polymorphisms (SNPs) within the promoter and intron1 binding sites of the PXR regulatory region lead to an impaired expression of PXR and CYP3A4 and that this has been connected to drug-induced liver damage after antituberculosis therapy [109]. SNPs present in PXR exons are responsible for modifications of the LBD or DBD, affecting the interactions with ligand compounds or DNA, whereas SNPs in the noncoding sequences usually affect transcription, post-transcriptional modifications, and translation [23]. The so called NRI12-rs7643645 polymorphism is located within the intron1b region, near to the promotor sequence that specifically binds the hepatic nuclear factor 4\(\alpha\) (HNF4\(\alpha\)). A loss of this binding site has been observed in consequence of the mutation from A to G allele NRI12-rs7643645 and causes a loss of 82% HNF4\(\alpha\)-related genes in males. In females, a suppression of a lower percentage (52%) of transcription has been noticed, accompanied by an upregulation of a small number of HNF4\(\alpha\)-related genes [109]. It should be noticed that the lack of HNF4\(\alpha\) in the liver seems to be associated with impaired lipid, glucose, cholesterol, and BA homeostasis and is considered as a pivotal regulator of hepatic transcriptome.