Research Article Details
| Article ID: | A10946 |
| PMID: | 31109939 |
| Source: | Diabetes |
| Title: | The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism. |
| Abstract: | It has been appreciated for many years that there is a strong association between metabolism and immunity in advanced metazoan organisms. Distinct immune signatures and signaling pathways have been found not only in immune but also in metabolic cells. The newly discovered DNA-sensing cGAS-cGAMP-STING pathway mediates type I interferon inflammatory responses in immune cells to defend against viral and bacterial infections. Recent studies show that this pathway is also activated by host DNA aberrantly localized in the cytosol, contributing to increased sterile inflammation, insulin resistance, and the development of nonalcoholic fatty liver disease (NAFLD). Potential interactions of the cGAS-cGAMP-STING pathway with mTORC1 signaling, autophagy, and apoptosis have been reported, suggesting an important role of the cGAS-cGAMP-STING pathway in the networking and coordination of these important biological processes. However, the regulation, mechanism of action, and tissue-specific role of the cGAS-cGAMP-STING signaling pathway in metabolic disorders remain largely elusive. It is also unclear whether targeting this signaling pathway is effective for the prevention and treatment of obesity-induced metabolic diseases. Answers to these questions would provide new insights for developing effective therapeutic interventions for metabolic diseases such as insulin resistance, NAFLD, and type 2 diabetes. |
| DOI: | 10.2337/dbi18-0052 |
| 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 |
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | 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 |
|---|
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D612 | Rapamycin | Miscellany | -- | Immunosuppressants; Methylmalonyl CoA mutase stimulants; MTOR protein inhibitors; T lymphocyte inhibitors | -- | Under investigation | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |