Novel β‐catenin/farnesoid X receptor interaction regulates hepatic bile acid metabolism during cholestasis
Authors: Laurent Ehrlich, Shannon S. Glaser
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article on Page 955 This material is the result of work supported by resources at the Central Texas Veterans Health Care System. The content is the responsibility of the author(s) alone and does not necessarily reflect the views or policies of the Department of Veterans Affairs or the US government. β‐Catenin, a 781–amino acid, 85.5‐kDa scaffold protein, serves a range of molecular functions including cell‐to‐cell adhesion to gene transcription. It is highly evolutionarily conserved and indispensable for embryonic development. β‐Catenin is a binding partner of adenomatous polyposis coli protein, responsible for degrading β‐catenin to prevent its nuclear accumulation and gene transcriptional function (Fig. 1A). Adenomatous polyposis coli is mutated in ∼80% of colon cancers and is the hereditary mutated gene in familial adenomatous polyposis disorder. β‐Catenin is also important for liver development and carcinogenesis. As a key binding partner of E‐cadherin in adherens junctions, β‐catenin links the cytoskeleton of adjacent epithelial cells. How β‐catenin carries out both cytoplasmic and nuclear functions, and the consequences of its dysregulation, remain a subject of much debate.1 In this original article by Thompson and colleagues, the authors describe a finely tuned interplay between β‐catenin and farnesoid X receptor (FXR) in response to cholestatic injury.2Figure 1: Various nuclear roles of β‐catenin following external Wnt signaling. (A) The canonical Wnt signaling pathway involves nuclear dimerization of β‐catenin and TCF4. (B) Following hypoxic conditions, β‐catenin ceases to bind to TCF4 and instead binds with HIF‐1α to direct activation of genes containing a hypoxia response element. (C) During cholestasis in the presence of high bile acid concentrations, TCF4 binding decreases retinoid X receptor‐α/FXR heterodimer formation; and transcription of downstream targets occurs, resulting in suppression of bile acid synthesis and altered transport. Knockout of β‐catenin expression during cholestatic injury reduces β‐catenin/FXR complex, activates FXR to decrease total bile acids, and alleviates hepatic injury. Abbreviations: APC, adenomatous polyposis coli; BA, bile acid; LRP, low‐density lipoprotein receptor–related protein; RXRα, retinoid X receptor‐alpha. (Images adapted from motifolio.com.)Canonical Wnt Signaling β‐Catenin is the key player in canonical Wnt signaling. The Wnt gene encodes a cysteine‐rich protein that is secreted into the extracellular matrix and binds surface receptor Frizzled and low‐density lipoprotein receptor–related protein coreceptors (Fig. 1A). Wnt signaling is key for proper morphogenesis during embryonic development. In the liver, the Wnt–β‐catenin signaling pathway also acts as a morphogen. β‐Catenin expression is directly proportional to liver size, and Wnt‐triggered gene transcription controls hepatocyte cell‐cycle entry.3 Even more interesting, after embryonic development, Wnt–β‐catenin signaling seems to play an important role in maintenance and turnover in stem‐cell populations. In the liver, Wnt–β‐catenin signaling occurs in oval cells located near the portal tracts. It is believed that Wnt–β‐catenin is crucial for oval cell maintenance, turnover, and differentiation into cholangiocytes and/or hepatocytes following injury.4 Lack of β‐catenin has a profound effect on bile duct morphology. Bile canaliculi are dilated and “tortuous” and lack appropriate surface microvilli necessary for proper transport, resulting in intrahepatic cholestasis.5 Adherens junctions remain intact, most likely because γ‐catenin replaces β‐catenin as an E‐cadherin partner.6 However, there is a loss of claudin‐2, indicating there may be a defect in crosstalk between tight junction and adherens junction.5 Thus, the resulting cholestasis from liver‐specific β‐catenin knockout is most likely due to aberrant morphology and perhaps impaired contractility as a result of epithelial barrier disruption. FXR: Nuclear Bile Acid Receptor To a certain extent, the relationship between FXR and Wnt–β‐catenin signaling has been hinted at in the past but not conclusively established. FXR is the predominant nuclear bile acid receptor and regulates gene transcription of important players of bile acid synthesis and metabolism. As a major site of bile acid recycling in the enterohepatic circulation, it comes as little surprise that FXR activation is protective against adenomatous polyposis coli–deficient adenoma tumorigenesis.7 In the liver, β‐catenin and FXR expression are inversely proportional in human hepatocellular carcinomas, and overexpression of an oncogenic form of β‐catenin results in cholestasis, likely through down‐regulation of FXR expression.8 FXR coimmunoprecipitates with β‐catenin and negatively regulates Wnt signaling through competitive antagonism of T‐cell factor 4 (TCF4), β‐catenin's nuclear binding partner, to activate Wnt gene targets (Fig. 1C).8 Hypoxic Wnt Signaling The role of β‐catenin in hepatoprotection is controversial and may depend on the type of liver disease. For example, while β‐catenin is an oncogene in hepatocellular carcinoma, it plays a protective role in hypoxic models of injury such as partial hepatectomy or ischemic‐reperfusion injury. Hepatocyte‐specific β‐catenin deficiency sensitized the liver to higher oxidative damage, necrosis, and apoptosis. Under hypoxic conditions, β‐catenin is diverted from its classical TCF4 binding partner and the TCF4 gene targets and instead complexes with hypoxia‐inducible factor 1 alpha (HIF‐1α) and binds hypoxia response elements to promote angiogenesis and antioxidant changes (Fig. 1B). The signaling appears to be triggered by classical Wnt receptor binding, but it is unclear mechanistically how β‐catenin switches from TCF4‐dependent signaling to the HIF‐1α‐guided pathway.9 On the other hand, in acute liver injury induced by lipopolysaccharide, mice lacking β‐catenin were resistant to injury and apoptosis. This protection is due to loss of the inhibitory association between β‐catenin and the nuclear factor‐κB subunit p65 in the cytoplasm, which normally prevents p65 nuclear translocation. Absence of this association in β‐catenin knockout mice led to earlier and protracted p65 translocation and transcription of prosurvival target genes. Bile Acid Homeostasis In this original article, Thompson and colleagues expand on the role of β‐catenin in bile acid homeostasis. Liver‐specific β‐catenin knockout mice are cholestatic at baseline, for reasons described above; however, they are paradoxically protected from cholestatic liver insults such as bile duct ligation and a 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine diet. There is less inflammation and neutrophil recruitment in mice lacking β‐catenin following cholestatic injury and, as a result, fewer biliary infarctions, less hepatocyte apoptosis, and reduced liver size. In the presence of increased bile acid levels, lack of β‐catenin appears to decrease production of reactive oxygen species, opposite from the hypoxic injury models described above.9 Furthermore, classical features of cholestatic disease were dampened such as the number of activated myofibroblasts, the amount of collagen deposition/fibrosis, and the level of atypical ductular proliferation. Interestingly, exogenous inhibitors of β‐catenin targeted directly to hepatocytes indicated that reduced atypical ductular proliferation was secondary to reduced liver damage rather than directly due to lack of β‐catenin in cholangiocytes. However, it is unclear if perhaps oval cells also lack β‐catenin expression in these models as an explanation for reduced Wnt‐directed oval‐cell proliferation and differentiation.4 As described above, the relationship between β‐catenin and FXR has been established.8 However, the mechanism by which β‐catenin and FXR maintain homeostasis following cholestatic injury sheds light on their larger role in the liver. For example, following hypoxic injury, where β‐catenin expression is protective, β‐catenin trades its classical binding partner TCF4 and the TCF4‐dependent signaling pathway with HIF‐1α and its anti‐inflammatory, anti‐oxidant pathway (Fig. 1B). In this article, we see that β‐catenin competitively binds with FXR and suppresses FXR‐mediated gene transcription of bile acid signaling pathways (Fig. 1C). While lack of β‐catenin imposes cholestasis under normal conditions, due to abnormal bile duct morphology, lack of β‐catenin is protective under cholestatic injury conditions, apparently through disinhibition of FXR. The data presented in this article provide a broad and comprehensive understanding of the interplay between canonical Wnt signaling and FXR signaling. For example, the small heterodimer partner (SHP) promoter, a gene that is hepatoprotective,10 contains binding sites for both TCF4 and FXR. β‐Catenin binds with TCF4 on the SHP promoter, presumably to restrict induction of its expression; and β‐catenin also binds to FXR and prevents its ability to transactivate SHP expression. Following cholestatic injury, an increase in bile acids activates the FXR, which dissociates from β‐catenin and binds to the SHP promoter, as well as other bile acid signaling targets, to drive its expression. In mice lacking β‐catenin, FXR activity is potentiated by bile acid signaling/FXR agonism due to its already dissociated state. In conclusion, there remains a need for the elucidation of a clear mechanistic understanding of β‐catenin dynamics under various conditions. The authors of this article suggest that posttranslational modifications and stoichiometric ratios of binding partners may play a role. Furthermore, the article suggests that different β‐catenin complexes alter chromatin structure to affect disparate gene target pathways. The original work presented here portrays a robust cellular response to various environmental insults that is coordinated through β‐catenin activity that might be targeted therapeutically during the progression of cholestatic liver diseases.