Current understanding and dispute on the function of the Wnt signaling pathway effector TCF7L2 in hepatic gluconeogenesis

摘要

Abstract Approximately 10 years ago, the Wnt signaling pathway effector TCF7L2 (=TCF-4) was recognized as a type 2 diabetes (T2D) risk gene through a genome wide association study (GWAS). As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups, great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas, liver and adipose tissues. Although these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis, studies conducted to date have also generated controversial suggestions. Here I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies. I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk, a gain-of-function event versus a loss-of-function event. This will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives. Keywords β-Catenin ; Gluconeogenesis ; Insulin ; TCF7L2 ; Transgenic mice ; Type 2 diabetes ; Wnt prs.rt("abs_end"); The recognition of TCF7L2 as a diabetic risk gene Although several early investigations have indicated the role of Wnt signaling pathway in the production and function of certain metabolic hormones, 1 , 2 , 3 and 4 the intensive global attention to the function of this pathway on glucose homeostasis started in 2006, after a genome wide association study (GWAS) performed by Grant and colleagues revealed the linkage between the polymorphisms of the Wnt signaling pathway effector TCF7L2 and the risk of type 2 diabetes (T2D). 5 Back to 1999 and 2003, investigators had revealed that a region on chromosome 10q is linked to T2D susceptibility. 6 and 7 Briefly, using a variance-components technique for conducting multi-point linkage analyses in a Mexican American population, Duggirala et?al obtained evidence that there is a T2D susceptibility locus on chromosome 10q. 6 In 2003, a genome wide linkage study performed by Reynisdottir et?al in an Icelandic population yielded the linkages of T2D susceptibility to regions on chromosome 5q34-q35.2, 12q, as well as10q. 7 Three years later, Grant et?al defined the genetic linkage on chromosomal 10q. 5 Grant et?al genotyped 228 microsatellite markers in a cohort of Icelandic subjects with T2D and healthy controls across a 10.5-Mb interval on the chromosome 10q. The microsatellite, DG10S478, located within the intron 3 region of the TCF7L2 gene (previously known as TCF-4 ) was found to be associated with the T2D susceptibility. This correlation was then replicated in a U.S. cohort as well as a Danish cohort. Furthermore, two single nucleotide polymorphisms (SNPs) known as rs12255372 and rs7903146 were found to be in strong linkage disequilibrium with DG10S478 and also showed similar robust associations with T2D susceptibility. By comparing with the non-carriers, they calculated that heterozygous and homozygous carriers of the at-risk alleles have relative risks of T2D of 1.45 and 2.41, respectively. 5 Importantly, this association has been replicated by numerous investigations among different ethnic populations. 8 , 9 , 10 , 11 , 12 , 13 and 14 Studies have also revealed the linkage between these T2D susceptibility SNPs with cardiovascular and other complications of T2D. 15 and 16 Wnt signaling pathway and its key effector β-catenin/TCF The Wnt signaling pathway was initially identified in cancer research and embryologic developmental studies 17 and 18 ; while the physiological role of Wnt signaling in metabolic homeostasis and its implications in metabolic disorders have received broad attention since last decade, 1 , 19 and 20 especially after TCF7L2 is recognized as an important T2D risk gene. 5 The key effector of Wnt pathway is β-catenin (β-cat)/TCF (cat/TCF), formed by free β-cat and a member of the TCF transcription factor family, including TCF7L2. 21 TCFs possess a high mobility group box (HMG) DNA binding domain while β-cat provides the transcriptional activation domain. In resting cells, free β-cat levels are tightly controlled by the proteasome-mediated degradation process ( Fig.?1 A, left panel). This involves the actions of the degradation complex on β-cat. The key components of this degradation complex are two tumor suppressors, adenomatous polyposis coli (APC) and axin/conduction; as well as two protein kinases, the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) and casein kinases 1α (CK-1α). Following binding of a canonical Wnt ligand to the Frizzled receptor and LRP5/6 co-receptor, the degradation complex is dissociated, with the participation of the protein na