# The Nuclear Receptor PXR in Chronic Liver Disease
## 4 PXR and Liver Steatosis  
Nonalcoholic fatty liver disease (NAFLD) comprises a variable degree of liver dysfunction ranging from simple steatosis, where lipid droplets accumulate within hepatocytes, to nonalcoholic steatohepatitis (NASH), characterized by hepatic inflammation and fibrosis [58; 59]. NAFLD has become a public health issue of increasing relevance, due to incorrect lifestyle and food habits, characterized by the excessive intake of fat and sugar [60]. Being usually not accompanied by visible pathological signs, NAFLD is hardly diagnosed in the initial phase, whereas when reaching the final stage of NASH it could decline to liver cirrhosis and hepatocellular carcinoma [59]. One common feature of liver steatosis of all degrees is the accumulation of lipids in the cytoplasm of hepatocytes, due to an impaired modulation of lipid intake, de novo lipogenesis, and lipid metabolism [36]. Since PXR is involved in the regulation of lipid metabolism, some studies have focused on investigating its role in NAFLD and NASH (Table 2). Although some experimental findings demonstrated a correlation between NAFLD and the dysregulation of genes controlled by PXR [61], this topic is still debated, and controversial results have been obtained by both preclinical and clinical studies. Some PXR gene variants have been correlated with NAFLD severity and could be responsible for the progression towards more severe disease stages [62]. Several studies demonstrated that a significant activation of PXR in mice fed with a diet rich in fat and cholesterol promoted the typical hallmarks of NAFLD and NASH, such as steatosis, inflammation, and lipotoxicity, suggesting that PXR activation seems to in \begin{table}
\begin{tabular}{c c c} \hline \hline
**Effect** & **Model** & **Reference** \\ \hline Increase in PXR gene and protein levels & Patients with & [28; 29] \\ PXR downregulation in the late stage of & obstructive cholestasis & Children with biliary atresia & [30] \\ \hline PXR upregulation in the first stages and & & \\ downregulation in the late stages of & & BDL rats & [43] \\ cholestatic disease & & \\ A SNP the exon 9 of PXR is weakly correlated & & \\ with the progression and severity of PBC & & \\ Reduction in PXR expression with respect to & PBC patients grade III and IV & [48] \\ healthy subjects & & \\ Bezafibrate increases PXR gene expression & & \\ exerting anticholestic effect & & \\ Rifampicin-induced PXR activation mediates & & \\ the upregulation of UGT1A1 and MRP2 & & \\ PXR overexpression correlates with SULT2A1 & & \\ upregulation only in PBC patients & & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Main studies investigating the involvement of PXR in cholestatic liver diseases. crease lipid accumulation in the liver, promoting a \"fatty phenotype\" [63; 64; 65]. Consistently, a reduction in high-fat diet (HFD)-induced obesity was observed in PXR KO mice and was correlated with an upregulation of FGFI5 expression, which suppresses the synthesis of bile acids and reduces lipid absorption and triglycerides in the liver [66]. Accordingly, PXR resulted in being upregulated in the pediatric patients enrolled in the TONIC trial, affected by fibrosis associated with NAFLD. Based on the prognostic relevance of fibrosis in NAFLD patients, PXR has been suggested to have a relevant clinical implication [67; 68]. A transcriptome analysis revealed a significant difference between mice fed with HFD and mice fed with a low-fat diet [69]. In detail, [PERSON] and collaborators analyzed PXR and CAR-modulated CYP3A expression and activity, observing that the administration of HFD activated PXR, inducing both the expression and enzymatic activity of CYP3A11, the murine homologue of the human CYP3A4 [70]. The strong correlation between CYP3A11 expression and PXR activation was observed in all the stages of the disease, from the uncomplicated steatosis to the development of NASH and liver fibrosis [69]. This transcriptional effect on CYP3A11 was not related to CAR activity.