Research Article Details
| Article ID: | A08330 |
| PMID: | 32150756 |
| Source: | Hepatology |
| Title: | N6 -Methyladenosine Reader Protein YT521-B Homology Domain-Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes. |
| Abstract: | BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD. |
| DOI: | 10.1002/hep.31220 |
| 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 |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T22 | Stearoyl-CoA desaturase | SCD | inhibitor | Enzyme | O00767 | SCD_HUMAN | 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 |