Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis.

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.

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

B cell dysfunction due to obesity can be associated with alterations in the levels of micro-RNAs (miRNAs). However, the role of miRNAs in these processes remains elusive. Here, we show that miR-802 is increased in the pancreatic islets of obese mouse models and demonstrate that inducible transgenic overexpression of miR-802 in mice causes impaired insulin transcription and secretion. We identify Foxo1 as a transcription factor of miR-802 promoting its transcription, and NeuroD1 and Fzd5 as targets of miR-802-dependent silencing. Repression of NeuroD1 in β cell and primary islets impairs insulin transcription and reduction of Fzd5 in β cell, which, in turn, impairs Ca2+ signaling, thereby repressing calcium influx and decreasing insulin secretion. We functionally create a novel network between obesity and β cell dysfunction via miR-802 regulation. Elucidation of the impact of obesity on microRNA expression can broaden our understanding of pathophysiological development of diabetes. Obesity predisposes to type 2 diabetes, but the mechanisms of obesity-associated β cell dysfunction are incompletely understood. Here the authors report that obesity increases the levels of miR-802, which impairs insulin transcription and secretion by targeting NeuroD1 and Fzd5.

Obesity-induced overexpression of miR-802 impairs insulin transcription and secretion

Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis.

Type 2 diabetes mellitus (T2DM) has become a major global public health issue in the twenty-first century and its incidence has increased each year. Wnt signaling pathways are a set of multi-downstream signaling pathways activated by the binding of Wnt ligands to membrane protein receptors. Wnt signaling pathways regulate protein expression and play important roles in protecting the body's normal physiological metabolism. This review describes Wnt signaling pathways, and then aims to reveal how Wnt signaling pathways participate in the occurrence and development of T2DM. We found that Wnt/c-Jun N-terminal kinase signaling was closely associated with insulin resistance, inflammatory response, and pancreatic β-cell and endothelial dysfunction. β-catenin/transcription factor 7-like 2 (TCF7L2)-mediated and calcineurin/nuclear factor of activated T cells-mediated target genes were involved in insulin synthesis and secretion, insulin degradation, pancreatic β-cell growth and regeneration, and functional application of pancreatic β-cells. In addition, polymorphisms in the TCF7L2 gene could increase risk of T2DM according to previous and the most current results, and the T allele of its variants was a more adverse factor for abnormal pancreatic β-cell function and impaired glucose tolerance in patients with T2DM. These findings indicate a strong correlation between Wnt signaling pathways and T2DM, particularly in terms of pancreatic islet dysfunction and insulin resistance, and new therapeutic targets for T2DM may be identified.

Role of Wnt signaling pathways in type 2 diabetes mellitus.

Our aim was to test whether pharmacological inhibition of cycloxygenase-2 (COX-2) reverses non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus (T2DM) rats via suppression of the non-canonical Wnt signaling pathway expression. Twenty-four male Sprague-Dawley rats were randomly distributed to two groups and were fed with a high fat and sucrose (HF-HS) diet or a normal chow diet, respectively. After four weeks, rats fed with a HF-HS diet were made diabetic with low-dose streptozotocin. At the 9th week the diabetic rats fed with a HF-HS diet or the non-diabetic rats fed with a normal chow diet were further divided into two subgroups treated with vehicle or celecoxib (a selective COX-2 inhibitor, 10 mg/Kg/day, gavage) for the last 4 weeks, respectively. At the end of the 12th week, rats were anesthetized. NASH was assessed by histology. Related cytokine expression was measured at both the protein and gene levels through immunohistochemistry (IHC), Western blot and real-time PCR. T2DM rats fed with a HF-HS diet developed steatohepatitis and insulin resistance associated with elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin levels and the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 were all significantly increased in the T2DM-NASH group compared with the control and control-cele group. Hepatic injury was improved by celecoxib in T2DM-NASH-Cele group indicated by reduced serum ALT and AST levels and hepatic inflammation was reduced by celecoxib showed by histology and the NAFLD activity score (NAS). Serum related metabolic parameters, HOMA-IR and insulin sensitivity index were all improved by celecoxib. The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 expression were all suppressed by celecoxib in T2DM-NASH-Cele group. The results of the present study indicated that celecoxib ameliorated NASH in T2DM rats via suppression of the non-canonical Wnt5a/JNK1 signaling pathway expression.

/pdf/celecoxib-ameliorates-non-alcoholic-steatohepatitis-in-type-3oo2f42pi1.pdf

Celecoxib ameliorates non-alcoholic steatohepatitis in type 2 diabetic rats via suppression of the non-canonical Wnt signaling pathway expression.

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Celecoxib ameliorates non-alcoholic steatohepatitis in type 2 diabetic rats via suppression of the non-canonical Wnt signaling pathway expression.