Research Article Details
| Article ID: | A14622 |
| PMID: | 29319180 |
| Source: | J Cell Physiol |
| Title: | WISP1 promotes non-alcoholic fatty liver disease and skeletal muscle insulin resistance via TLR4/JNK signaling. |
| Abstract: | Wnt1-inducible signaling pathway protein-1 (WISP1) is a Cyr61/CTGF/NOV (CCN) family matricellular protein involved in adipogenesis and low-grade inflammation in obesity. However, the roles of WISP1 in hepatic steatosis and insulin resistance in skeletal muscle remain elusive. Mouse primary hepatocytes and differentiated mouse skeletal muscle cells (C2C12) were treated with various concentrations of WISP1 and the functions and signaling pathways were analyzed by Western blot analysis. In vivo transfection for WISP1 knockdown was also performed to examine the effects of WISP1 on hepatic steatosis and skeletal muscle insulin resistance. Knockdown of WISP1 in high-fat diet-fed C57BL/6 mice significantly reduced (0.45-0.5%; p < 0.05) inflammation and JNK phosphorylation (45-50%; P < 0.01) and attenuated hepatic steatosis (approximately 55%; p < 0.001) and skeletal muscle insulin resistance (30-40%; p < 0.05). Treatment with WISP1 significantly induced inflammation (hepatocytes: approximately 500%; p < 0.01, C2C12 cells: approximately 500%; p < 0.01) and JNK phosphorylation (hepatocytes: approximately 200%; p < 0.01, C2C12 cells: approximately 280%; p < 0.01) in mouse primary hepatocytes and C2C12 mouse skeletal muscle cells. Moreover, it increased lipogenesis-associated gene expression (200-300%; p < 0.01) and accumulation of triglycerides (approximately 320%; p < 0.01) in hepatocytes, and suppressed insulin signaling (approximately 50%; p < 0.01) in C2C12 cells. These WISP1-induced effects were significantly abrogated in NFκB-, JNK-, and TLR4-knockdown hepatocytes (p < 0.05) and C2C12 cells (p < 0.05). These results indicate that WISP1 contributes to hepatic steatosis and skeletal muscle insulin resistance through a TLR4-activated inflammation/JNK signaling pathway and could be a useful therapeutic target for treatment of non-alcoholic fatty liver disease and type 2 diabetes. |
| DOI: | 10.1002/jcp.26449 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |