Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases

Abstract

Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation.

Keywords: Wnt signalling; cardiovascular disease; diabetes; kidney disease; metabolic disease; non-alcoholic fatty liver disease.

Figure 1.

Wnt signalling pathways and their interactions. The canonical pathway is defined by the intracellular accumulation of β-catenin, and its resulting translocation to the nucleus where it regulates expression of target genes. The non-canonical pathway is defined by its β-catenin-independent actions ranging from intracellular signalling and expression of target genes. The non-canonical pathway can inhibit the canonical pathway at multiple levels. Activation of the Wnt/Ca²⁺ pathway has been demonstrated to affect gene transcription through NFAT, but can also inhibit β-catenin signalling through NLK. Downstream of the PCP pathway, RhoA regulates cytoskeletal rearrangement and cell survival; in addition, Rac and subsequent c-JNK activation positively regulates AP-1-dependent gene transcription. The complexity of Wnt signalling is compounded by the multiple extracellular factors, and co-receptors capable of influencing both canonical and non-canonical signalling. sFRP: secreted frizzled-related protein; WIF: Wnt inhibitory factor; DKK: dickkopf-related protein; Dsh: Dishevelled; CK1: casein kinase 1; APC: adenomatous polyposis coli; Siah2: E3 ubiquitin-protein ligase; GSK3β: glycogen synthase kinase 3 beta; β-TrCP: beta-transducin repeat containing protein; CAMKII: Ca²⁺/calmodulin-dependent protein kinase II; TAK1: mitogen-activated protein kinase kinase kinase 7; PKC: protein kinase C; PLC: phospholipase C; DAAM1: dishevelled-associated activator of morphogenesis 1; ROCK: rho-associated protein kinase; RhoA: Ras homolog gene family, member A; Rac: Ras-related C3 botulinum toxin substrate; NFAT: nuclear factor of activated T-cells; NLK: Nemo-like kinase; AP-1: activator protein 1; JNK: Jun N-terminal kinase.

Figure 2.

Overarching hypothesis. Chronic metabolic disease involving fibrosis and extracellular matrix deposition have dysregulated Wnt signalling and a tendency to have excessive activation of the canonical Wnt signalling pathway. Chronic metabolic diseases involving inflammation and lipid accumulation have dysregulated Wnt signalling and a tendency towards excessive activation of the non-canonical Wnt signalling pathway. Excessive non-canonical signalling has also been shown to drive insulin resistance in adipose tissue and liver. The role of canonical and non-canonical Wnt signalling in kidney disease is less clear. However, it appears to be contingent on over/under activation of either pathway both contributing to chronic kidney disease. Wnts are implicated in obesity, type II diabetes (insulin resistance), NAFLD, CKD and cardiovascular disease through lipid accumulation and fibrosis. The intricate balance of both arms of the Wnt signalling pathways with fibrosis, inflammation and lipid accumulation may contribute to the development of these chronic metabolic diseases. NAFLD: non-alcoholic fatty liver disease; CKD: chronic kidney disease.