# The Nuclear Receptor PXR in Chronic Liver Disease
## 3 PXR and Cholesterasis
### PXR and Autoimmune Cholesterate Diseases  
The most diagnosed chronic cholestatic diseases are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), both characterized by an immune-mediated damage affecting the small intrahepatic bile duct (PBC) or the intra- and extrahepatic large bile ducts (PSC) [32]. In addition to the immune-mediated damage, the pathogenic features of PBC and PSC include inflammation induced by BA toxicity and subsequent wound-healing responses with peculiar fibrotic outcomes [27; 39]. PBC is a rare condition that predominantly affects women with a 10:1 ratio to males. Genetic factors, such as the above-stated female sex or variants in the human leukocyte antigens (HLA) locus, are known to influence the development of this disease [27; 39]. Interestingly, the immune attack to biliary epithelial cells (BECs) is due to a loss of tolerance towards the modified E2 subunit of the mitochondrial pyruvate dehydrogenase complex (PDC-E2). This complex is recognized by antimitochondrial antibodies (AMAs) that, together with an infiltration of CD4+ and CD8+T cells, constitute the main pathogenic features of PBC [27; 39]. Aberrant modifications of the PDC-E2 complex are responsible for the loss of BECs integrity. In addition, an impairment of anion exchanger 2 (AE2) activity on BECs membrane could alter the pH of cholangiocarcinomaytes, creating an alkaline intracellular environment triggering cyclases able to acidify bile salts [39; 44]. Consequently, BECs or cholangiocarcinomaytes undergo apoptotic processes since they are sensitive to the action of cytotoxic BAs [39]. PSC is a rare condition affecting EU habitants with a ratio of 1:2000 [45]. Fibrosis and inflammation are responsible for multifocal biliary strictures, orchestrated by hepatic stellate cells, portal macrophages, and cholangiocarcinomaytes [45]. Although the pathological mechanisms behind its development are not completely understood, there is a general consensus that other autoimmune diseases--for example, inflammatory bowel diseases (IBD)--represent a risk factor for PSC, and the senescence of cholangiocarcinomaytes is directly associated to its severity [27; 46]. Much evidence demonstrated that PXR expression is modulated in both PBC and PSC (Table 1). While alterations in PXR gene expression are known to play a significant role in the prognosis of PSC, a study by [PERSON] and collaborators demonstrated that the genetic background of PXR, specifically a single nucleotide polymorphism (SNP) C/A in exon 9 of 3\({}^{\prime}\)-UTR of NR1L2/PXR, is weakly correlated with the progression and severity of PBC [47]. Furthermore, it has been demonstrated that in PBC patients grade III and IV, PXR expression is reduced by 40-60% with respect to healthy subjects [48]. A study investigating the use of bezafibrate, a dual PPAR/PXR agonist, in PBC patients found a significant increase in PXR gene expression after treatment and suggested that this decrease may contribute to the anticholestatic activity of bezafibrate [49]. The common trait of PBC and PSC is the loss of tolerance against self-molecules, thus triggering an increased activation of the immune system and production of proinflammatory mediators, sometimes accompanied by extrahepatic autoimmune manifestations [50]. The increased amount of toxic BAs characterizing these diseases leads to the injury of cholangiocarcinomaytes and activates a signaling cascade that sustains the release of proinflammatory cytokines and chemokines [51; 52]. Notably, PBC patients show an elevated number of toll-like receptors (TLRs) on BECs. Upon TLR-ligand binding, a recruitment of leukocytes to the non-immune tolerated area on cholangiocarcinomaytes occurs, probably AE2 or the PDC-E2 complex [52]. The stimulation of TLR-mediated signaling leads to the recruitment of pro-inflammatory factors, such as NF-kB factor and related cytokines [52].