Research Article Details
| Article ID: | A12206 |
| PMID: | 30562559 |
| Source: | Biochim Biophys Acta Mol Basis Dis |
| Title: | Hepatic mTOR-AKT2-Insig2 signaling pathway contributes to the improvement of hepatic steatosis after Roux-en-Y Gastric Bypass in mice. |
| Abstract: | Roux-en-Y Gastric Bypass (RYGB) remains one of the most effective options in treatment of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are not clear yet. Here, we evaluated the relationship among hepatic mechanistic target of rapamycin (mTOR)-AKT2-insulin-induced gene 2 (Insig2) signaling, lipogenic transcription factors and lipid synthesis enzymes in obese mice with or without RYGB operation. Hepatic mTOR activity and Insig2a were stimulated, while AKT2, sterol response element-binding protein 1c (SREBP1c), peroxisome proliferator-activated receptor γ (PPARγ), lipogenic genes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were decreased by Roux-en-Y Gastric Bypass in both DMSO and rapamycin treated diet-induced obese (DIO) mice. Increment of hepatic lipogenesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in DIO mice. RYGB significantly improved high-fat diet- and rapamycin- induced hepatic steatosis by suppression of de novo lipogenesis. Administration of adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1 (Ad-S6K1) from tail vein improved hepatic steatosis. Infusion of Ad-S6K1 suppressed AKT2, SREBP1c, PPARγ, and lipogenesis-related genes while stimulating Insig2a in DIO mice. Ad-S6K1 decreased oleic acid-induced lipid deposition in primary mouse hepatocytes. Our results suggest that mTOR-AKT2-Insig2 signaling pathway contributes to the improvement effect of RYGB on hepatic steatosis induced by high-fat diet. |
| DOI: | 10.1016/j.bbadis.2018.12.014 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| 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 | |
|---|---|---|---|---|---|
| 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 | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | 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 |