Research Article Details
| Article ID: | A03682 |
| PMID: | 33903707 |
| Source: | Sci Rep |
| Title: | MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies. |
| Abstract: | Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms. The Let-7 family of microRNAs were one of the first to be discovered, and are closely related to metabolic processes. Bioinformatic analysis revealed that Prkaa2, the gene that encodes AMPK α2, is a predicted target of Let-7. Here we aimed to investigate whether Let-7 has a role in AMPKα2 levels in the NAFLD development in the offspring programmed by maternal obesity. Let-7 levels were upregulated in the liver of newborn mice from obese dams, while the levels of Prkaa2 were downregulated. Let-7 levels strongly correlated with serum glucose, insulin and NEFA, and in vitro treatment of AML12 with glucose and NEFA lead to higher Let-7 expression. Transfection of Let-7a mimic lead to downregulation of AMPKα2 levels, while the transfection with Let-7a inhibitor impaired both NEFA-mediated reduction of Prkaa2 levels and the fat accumulation driven by NEFA. The transfection of Let-7a inhibitor in ex-vivo liver slices from the offspring of obese dams restored phospho-AMPKα2 levels. In summary, Let-7a appears to regulate hepatic AMPKα2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams. |
| DOI: | 10.1038/s41598-021-88518-8 |
| 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 | |
|---|---|---|---|---|---|
| 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 |
| D545 | Pig placenta extract | Biological extract | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |