Research Article Details
| Article ID: | A13372 |
| PMID: | 30013137 |
| Source: | Nat Commun |
| Title: | Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis. |
| Abstract: | Insulin stimulates lipogenesis but insulin resistance is also associated with increased hepatic lipogenesis in obesity. However, the underlying mechanism remains poorly characterized. Here, we show a noncanonical insulin-Snail1 pathway that suppresses lipogenesis. Insulin robustly upregulates zinc-finger protein Snail1 in a PI 3-kinase-dependent manner. In obesity, the hepatic insulin-Snail1 cascade is impaired due to insulin resistance. Hepatocyte-specific deletion of Snail1 enhances insulin-stimulated lipogenesis in hepatocytes, exacerbates dietary NAFLD in mice, and attenuates NAFLD-associated insulin resistance. Liver-specific overexpression of Snail1 has the opposite effect. Mechanistically, Snail1 binds to the fatty acid synthase promoter and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27, thereby repressing fatty acid synthase promoter activity. Our data suggest that insulin pathways bifurcate into canonical (lipogenic) and noncanonical (anti-lipogenesis by Snail1) two arms. The noncanonical arm counterbalances the canonical arm through Snail1-elicited epigenetic suppression of lipogenic genes. Impairment in the insulin-Snail1 arm may contribute to NAFLD in obesity. |
| DOI: | 10.1038/s41467-018-05309-y |
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D010 | Amoxicillin | Chemical drug | DB01060 | -- | -- | Under clinical trials | Details |
| D395 | Zinc | Chemical drug | DB01593 | PSPH; CCS; HDAC1 cofactor; HDAC4 cofactor; INS; UTRN; ASPA cofactor; TP73 cofactor; A2M; AGT; APOBR; APOE; APOL1; C3; C5; CFB; CFH; CFI; CLU; CP; CPN2; DSP; F12; F13B; FGA; GSN; HBB; HPR; JUP; SELENOP; TTR; VTN | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |