# The Nuclear Receptor PXR in Chronic Liver Disease
## 3 PXR and Cholesterasis
### The Homeostasis of Bile Acids and PXR  
The liver is involved in the synthesis and transport of BAs [31], which are the result of cholesterol metabolism and act as emulsifiers to facilitate the absorption of liposome vitamins and lipids in the intestine, due to their amphiphilic nature [32; 33]. A dysfunction of their synthesis in hepatocytes, an impairment or obstruction of bile flow or atypical bile secretion in proximity of cholangiocarcinomaytes may induce cholestasis [32]. There are two main metabolic pathways for the synthesis of BAs, called either the _classical_ (neutral) or _alternative_ (acid) pathway [34]. Most of the BAs (about 75%) are produced by the former, including the primary BAs cholic acid (CA) and theendoacyclcholic acid (CDCA) [35]. Figure 2: Role of PXR in chronic liver diseases of different etiology. This pathway starts with a 7\(\alpha\)-hydroxylation of cholesterol by the rate limiting-enzyme CYP7A1, followed by the cleavage of the cholesterol side chain operated by CYP8B1, which determines the CA/CDCA ratio [34; 36]. Interestingly, preclinical in vivo studies demonstrated that the genetic deletion of CYP7A1 caused a high perinatal mortality and severe malnourishment of liposoluble vitamins and lipids in mice that survived. However, it has also been observed that surviving mice were able to produce BAs, although in low amount, thereby suggesting the presence of an alternative pathway [37]. Other studies demonstrated that this alternative pathway is mainly extra-hepatic and starts with a sterol 27-hydroxylation of cholesterol catalyzed by CYP27A1, followed by a 7-\(\alpha\) hydroxylation mediated by CYP7B1 producing three oxysterols [35; 37; 38]. The main outcome of the rate-limiting enzyme CYP7B1 is CDCA [34]. Once synthetized and before entering the bile canaliculi, the primary BAs are conjugated with glycine (in humans) and taurine (in humans and mice), released from hepatocytes, and stored in the gallbladder [32]. After meals, they are released into the small intestine to help the uptake of dietary lipids [39]. Once in the bowel, the gut microbiota is responsible for the deconjugation of primary BAs by the enzyme bile salt hydrolase (BSH) [34]. This reaction is followed by 7\(\alpha\)-dehydroxylation and epimerization, leading the conversion of primary unconjugated into secondary conjugated BAs, such as lithocholic acid, deoxycholic acid, and unsodeoxycholic acid (UDCA) [31; 32]. The 95% of BAs that are reabsorbed in the ileum by the enterohepatic cycle reach back to the liver [34]. Although a small portion of them passively cross the membrane of enterocytes, most of the BAs are reabsorbed by active transport by the apical sodium-dependent transporter (ASBT) [39]. Thanks to the basolateral organic solute transporter \(\alpha\beta\) (OST\(\alpha\beta\)), they enter the portal circulation and cross the hepatocyte membrane via the organic anion-transporting polypeptide (OATP) or the sodium-taurocholate cotransporting polypeptide (NTCP) [31; 39]. The remaining 5% is not absorbed in the ileum but reaches the colon, where the gut microbiota perform their deamination and dehydroxylation, allowing their passive reabsorption through the colonic epithelium. The BAs that are not reabsorbed by colon cells are excreted by feces [32; 39]. The complexity of these mechanisms, i.e., synthesis, conjugation, uptake, and export of BAs, explains the reason why their homeostasis needs to be finely regulated by several cellular pathways, including PXR-mediated signaling. A role of PXR in BA homeostasis was reported for the first time by [PERSON] and colleagues, who demonstrated that lithocholic acid and its metabolites could act as PXR activators [32; 40]. Nevertheless, some controversial findings have been reported so far regarding the concentration of BAs able to trigger PXR-mediated signaling.