Research Article Details
| Article ID: | A07199 |
| PMID: | 32585242 |
| Source: | Life Sci |
| Title: | IGFBP5 modulates lipid metabolism and insulin sensitivity through activating AMPK pathway in non-alcoholic fatty liver disease. |
| Abstract: | AIMS: Non-alcoholic fatty liver disease (NAFLD) characterized by excessive hepatic fat deposition is an increasing public health issue worldwide. Insulin resistance is a pivotal factor in NAFLD progression. Studies have found that IGFBP5 was related to insulin sensitivity. Nevertheless, the role of IGFBP5 in NAFLD remains unclear. MATERIALS AND METHODS: NAFLD models were established in vitro and in vivo by treating HepG2 cells with free fatty acids (FFA) and feeding mice with high-fat diet (HFD), respectively. IGFBP5 expression was then analyzed in these models. The effects and mechanism of IGFBP5 on lipid lipogenesis, fatty acid β-oxidation, and insulin resistance were investigated following IGFBP5 overexpression. Additionally, AMPK inhibitor compound C was used to treat HepG2 cells to confirm whether IGFBP5 functioned via activating AMPK pathway. KEY FINDINGS: IGFBP5 expression was decreased in both NAFLD models. IGFBP5 overexpression reduced levels of lipogenesis-associated proteins (SREBP-1c, FAS and ACC1), elevated expression of fatty acid β-oxidation-related genes (PPARα, CPT1A and ACOX1), decreased intracellular lipid droplets, promoted glucose uptake and glycogenesis, and activated IRS1/Akt and AMPK pathways. Administration of IGFBP5 vectors also decreased body weight and relieved liver damage in HFD-treated mice. In contrast, compound C abrogated the influences of IGFBP5 overexpression on cell models. SIGNIFICANCE: IGFBP5 dampened hepatic lipid accumulation and insulin resistance in NAFLD development via activating AMPK pathway. This study indicates that IGFBP5 may be a novel therapeutic agent for NAFLD. |
| DOI: | 10.1016/j.lfs.2020.117997 |
| 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 |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| 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 |
| 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 |