# The Nuclear Receptor PXR in Chronic Liver Disease
## 5 PXR and Liver Fibrosis  
Liver fibrosis is the main outcome of chronic liver diseases of different etiologies, such as excessive consumption of alcohol (ALD), viral hepatitis (HBV, HCV), steatosis, and cholestasis [80]. Mechanistically, fibrosis is the result of an impaired regenerative response to liver injury that leads to abnormal wound-healing processes, characterized by an accumulation of extracellular matrix (ECM) and inflammatory mediators [10; 80]. The main cellular features of this condition are hepatocyte damage, recruitment of inflammatory cells from circulation to the damaged site, and activation of the collagen-producing hepatic stellate cells (HSCs) [81]. Liver fibrosis represents a condition of liver damage affecting more than 800 million people worldwide [82]. Although reversible, fibrosis could progress to life-threatening conditions such as liver cirrhosis and HCC [80]. Fibrogenesis is regulated by the fine crosstalk between several liver cells, such as Kupffer cells, damaged hepatocytes, activated HSCs, monocyte-derived macrophages (MomFs), and other immune cells. In consequence of liver damage, several stimuli activate Kupffer cells, which produce interleukins (IL-6, IL-1\(\beta\)), chemokines (CCL5), growth factors (TGF\(\beta\), PDGF), and reactive oxygen species (ROS) that activate hepatic stellate cells (HSCs) and recruit inflammatory MomFs [82; 83]. The growth factor TGF-\(\beta\)1 is responsible for the phenotypic change of quiescent HSCs to myofibroblasts, able to secrete excessive amounts of ECM [80]. Furthermore, it is known that in patients with chronic liver disease, a particular subtype of MomFs (CD14 highCD16+) is responsible for the production of the pro-inflammatory cytokines TNF\(\alpha\) and IL-1\(\beta\), which also activate HSCs and contribute to disease progression [83]. The expression of PXR has been described in HSCs, monocytes, and resident macrophages, including Kupffer cells [84; 85]. Many studies on animal models of liver fibrosis and human specimens have been undertaken to unravel the possible role of PXR as an antifibrotic factor (Table 3). In carbon tetrachloride (CCl\({}_{4}\))-induced fibrosis, the PXR activator PCN is able to decrease fibrogenesis by downregulating the TGF-\(\beta\)1 pathway and reducing HSC activation [84; 86]. These findings have also been confirmed by experiments on human myofibroblasts, which demonstrated that the treatment with PXR activators leads to the inhibition of HSC differentiation to fibroblasts [10]. Similar effects have been demonstrated in other experimental models, such as animals treated with thioacetamide or fed with a high-fat-cholesterol (HFC) diet, where a reduction in PXR expression was observed with respect to controls. Accordingly, the treatment with PXR activators reduced fibrosis and improved liver functions (see [12] and references therein). \begin{table}
\begin{tabular}{l c c} \hline \hline
**Effect** & **Model** & **Reference** \\ HFD-induced PXR activation promotes steatosis, inflammation, and lipotoxicity & Mice fed with high fat and cholesterol diet & [65] \\ PXR genetic deletion reduces HFD-induced obesity and FGF15 expression, decreases the absorption of BAs and lipids and hepatic triglycerides & HFD-fed PXR KO mice & [66] \\ PXR expression is upregulated according to the degree of fibrosis & Pediatric and adult patients with NAFLD and fibrosis & [67; 68] \\ HFD induces PXR upregulation and increases CYP3A11 expression and activity & HFD-fed mice & [69] \\ PXR regulates the expression of SREBP1 and PPAR\(\alpha\), increases lipogenesis and reduces the oxidation of fatty acids & NAFLD mice and patients review & [74] \\ HFD reduces PXR activation and CYP3A4 expression due to an imbalance of the FGF21–PXR–CYP3A4 axis & Lipid-loaded Huh7 cells and HFD-fed mice & [76] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Main studies investigating the involvement of PXR in NAFLD/NASH.