Research Article Details
| Article ID: | A11428 |
| PMID: | 30898698 |
| Source: | Gene |
| Title: | Long noncoding RNA Mirt2 upregulates USP10 expression to suppress hepatic steatosis by sponging miR-34a-5p. |
| Abstract: | Non-alcoholic fatty liver disease (NAFLD) is always characterized by hepatic steatosis and insulin resistance. Dysregulated long noncoding RNAs regulate pathogenesis of NAFLD. However, the role of Mirt2 (long noncoding RNA myocardial infraction associated transcript 2) in NAFLD remains unclear. This original study aims to investigate the role of Mirt2 in hepatic steatosis and insulin resistance. Mirt2 was decreased in the livers of high-fat diet (HFD) mice, Ob/Ob, Db/Db, and fasting mice. Hepatic Mirt2 restoration attenuated hyperglycemia, insulin resistance and steatosis in the livers of obese mice, and Mirt2 inhibition promoted fasting hyperglycemia and lipid droplets accumulation in normal mouse livers. Furthermore, overexpression of Mirt2 resulted in suppression of miR-34a-5p, whereas knockdown of Mirt2 exerted opposite effects in the livers. Then, miR-34a-5p was a positive regulator of NAFLD by targeting USP10, which serves as a negative regulator of NAFLD. Overexpression of Mirt2 made miR-34a-5p mimic fail to reduce luciferase activity of USP10 3'-UTR, and this regulation was also demonstrated by Western blot. Similarly, overexpression of miR-34a-5p significantly let Mirt2 lost the ability to elevate USP10 protein level. Thus, Mirt2 can function as the sponge of miR-34a-5p. Moreover, Mirt2-mediated upregulation of USP10 protein expression can be reversed by silencing USP10. USP10 inhibition could abolish Mirt2 overexpression-induced suppression of glucose production and lipogenesis in hepatocytes. In conclusion, the decrease of Mirt2 expression contributed to hepatic insulin resistance and steatosis in obese mice, and Mirt2/miR-34a-5p/USP10 was involved in NAFLD development. Overexpression of Mirt2 might be a promising strategy for treatment of NAFLD. |
| DOI: | 10.1016/j.gene.2019.02.096 |
| 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 |
| 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 |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |