Wnt/-catenin signaling is emerging as a forerunner for its critical roles in many facets of human biology. Its roles in embryogenesis, organogenesis, and maintaining tissue and organ homeostasis demonstrate its munificent character. Its roles in pathological conditions such as cancer and other human disorders such as inflammatory disorders and fibrosis reveal its villainous disposition. In liver, it also maintains its dual personality and is clearly of essence in several physiological events such as development, regeneration, and growth. Its aberrant activation is also evident in many different tumors of the liver, and recent studies are beginning to identify its role in additional hepatic pathological conditions. It is contributing to liver physiology and pathology by regulating various basic cellular events, including differentiation, proliferation, survival, oxidative stress, morphogenesis, and others. This review discusses the contribution of the Wnt/-catenin signaling pathway in these events and simultaneously provides an essential overview of the major developments in the field of Wnt/-catenin and liver pathobiology. In addition, areas that are currently deficient or understudied are identified and discussed along with the avenues of translational and clinical relevance. (HEPATOLOGY 2007;45:1298-1305.) T he role of the Wnt/-catenin signaling pathway in liver biology has come to the forefront over the last several years. This development has been fueled by a number of studies examining this signaling pathway in the essential physiologic processes in the liver, elucidating its importance in development, growth, regeneration, zonation, metabolism, and oxidative stress. Likewise, there have been advances made in understanding the role of -catenin in the development of various liver diseases. Studies of pathological specimens and rodent models of liver diseases have demonstrated aberrations in the Wnt/-catenin signaling pathway in conditions ranging from hepatitis to hepatocellular carcinoma (HCC). Eventually this pathway has turned out to be among the central players in maintaining liver health.
-Catenin is the chief downstream effector of the canonical Wnt signaling pathway (Fig. 1). In the normal steady state, -catenin is targeted for degradation by phosphorylation at serine and threonine residues through the action of casein kinase I␣ and glycogen synthase kinase 3 (GSK3). 1,2 These proteins form a larger degradation complex with axin, adenomatous polyposis coli (APC), and diversin, all of which play a role in successful post-translational modification of -catenin, which allows for recognition and subsequent ubiquitination by the -transducin repeat-containing protein.
An activated state is brought about when Wnt binds to its receptor frizzled, inducing the formation of a ternary complex with low-density lipoprotein receptor related protein (LRP)5/6, ultimately leading to inactivation of GSK3 via activation of disheveled (Fig. 1). This leads to hypophosphorylation of -catenin and its release from complex with adenomas polyposis coli (APC) and axin, with ensuing nuclear translocation of -catenin where it binds to an HMG (High Mobility Group) box containing DNA-binding protein T cell factor/lymphoid-enhancing factor family member and controls transcription of various target genes. A listing of these targets can be found at: http://www.stanford.edu/ ϳrnusse/pathways/targets.html
Wnt/-Catenin Signaling Unique to Liver Cell Biology
Although -catenin is central to liver biology, as is discussed in the subsequent sections, its upstream effectors remain obscure in the liver. Classically, there are 19 Wnt and 10 Frizzled genes, but it is unlikely that all of Abbreviations: APC, adenomatous polyposis coli; CK, casein kinase; CYP, cyctochrome P450s; GSK3, glycogen synthase kinase 3; HGF, hepatocyte growth factor; LRP, low-density lipoprotein receptor related protein.