Research Article Details
| Article ID: | A07917 |
| PMID: | 32311490 |
| Source: | Free Radic Biol Med |
| Title: | Targeting DUSP7 signaling alleviates hepatic steatosis, inflammation and oxidative stress in high fat diet (HFD)-fed mice via suppression of TAK1. |
| Abstract: | The non-alcoholic fatty liver disease (NAFLD), as a critical liver disease, is still lack of effective treatments because the molecular mechanism revealing the NAFLD pathogenesis remains unclear. Dual specific phosphatase 6 (DUSP7) shows effects on inflammatory response and is a negative feedback mechanism of the mitogen-activated protein kinase (MAPK) superfamily, which are critical factors in regulating NAFLD progression. However, the effects of DUSP7 on hepatic steatosis are still not fully understood. Here, we found that DUSP7 functioned as a negative regulator of NAFLD and in various metabolic disorders. DUSP7 expression was markedly reduced in liver samples from patients with simple hepatic steatosis or non-alcoholic steatohepatitis (NASH), as well as in liver tissues from high fat diet (HFD)-challenged mice or genetically obese (ob/ob) mice. DUSP7 knockout markedly accelerated insulin resistance, glucose intolerance, liver dysfunction, fibrosis and hepatic steatosis in HFD-fed mice. In addition, inflammatory response was significantly exacerbated in HFD-challenged mice with DUSP7 deletion, which was associated with the elevated activation of nuclear factor-κB (NF-κB) and MAPKs signaling pathways. Moreover, oxidative stress was detected in liver of HFD-induced mice, and this phenomenon was aggravated in mice with DUSP7 knockout. Importantly, we demonstrated that DUSP7 physically interacted with transforming growth factor β (TGF-β)-activated kinase (TAK1). DUSP7 deletion considerably promoted the activation of TAK1 in mice after HFD feeding, contributing to the lipid deposition, inflammatory response and reactive oxygen species (ROS) production. Taken together, DUSP7 might function as a protective factor against NAFLD development and metabolic disorder through alleviating dyslipidemia, inflammation and oxidative stress by directly interacting with TAK1 in hepatocytes, which was involved in the suppression of fibrosis. Thus, we may provide an effective strategy for the treatment of hepatic steatosis via targeting DUSP7. |
| DOI: | 10.1016/j.freeradbiomed.2020.04.009 |
| 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 |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T43 | TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 | TAB1 | inhibitor | Kinase | Q15750 | TAB1_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| 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 |