Research Article Details
| Article ID: | A51841 |
| PMID: | 33785341 |
| Source: | Life Sci |
| Title: | Vascular endothelial growth factor B exerts lipid-lowering effect by activating AMPK via VEGFR1. |
| Abstract: | As an ambiguous member of vascular endothelial growth factor family, VEGF-B has long been poorly understood in its function. Recent researches showed VEGF-B isoforms exerted their metabolic effect through indirectly activating the VEGF-A/VEGFR2 pathway. Here, we report the lipid-lowing effect of VEGF-B via VEGFR1. We investigated the effect of VEGF-B on lipid metabolism in vivo and in vitro approaches. Treatment of mice with VEGF-B recombinant protein repressed HFD-induced body weight gain. This treatment also alleviated obesity associated hyperlipidemia and fatty liver disease. In the muscle and liver of VEGF-B-treated HFD mice were observed increased protein expression of carnitine palmitoyltransferase-1 (CPT-1) and the phosphorylation of ACC and AMP-activated protein kinase (AMPK). This effect was confirmed in HepG2 cells incubated with VEFG-B in which the increased AMPK activation and CPT-1 expression occurs due to activation of Calcium/calmodulin-dependent Protein Kinase β (CaMKKβ) by VEFG-B. VEGF-B increased expression of key genes responsible for lipid oxidation while reducing those for fatty acid synthesis in vivo and in vitro. In addition, the selective inhibitor of VEGFR1 blocked the lipid clearance effect of VEGF-B in HepG2. Our study unraveled unknown role of VEGF-B/VEGFR1 signaling in regulating lipid metabolism. Furthermore, our findings indicate that VEGF-B may have beneficial effects for the treatment of dyslipidemia. |
| DOI: | 10.1016/j.lfs.2021.119401 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| 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 |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | 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 | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D201 | L-Carnitine | Supplement | DB00583 | SLC22A4; SLC22A5; CRAT; MPO | -- | Under clinical trials | Details |
| D062 | Carnitine complex | Supplement | DB00583 | SLC22A4; SLC22A5; CRAT; MPO | -- | Under clinical trials | Details |
| D055 | Calcium | Chemical drug | DB01373 | CAST; COMP; CP; BMP4; MGP | -- | Under clinical trials | Details |