Research Article Details
| Article ID: | A08450 |
| PMID: | 32105829 |
| Source: | Free Radic Biol Med |
| Title: | 17β-estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance. |
| Abstract: | The prevalence and severity of nonalcoholic fatty liver disease (NAFLD) is higher in men and postmenopausal women compared to premenopausal women, suggesting a protective role for ovarian hormones. Diet-induced obesity and fatty acids surplus promote mitochondrial dysfunction in liver, triggering oxidative stress and activation of c-Jun N-terminal kinase (JNK) which has been related to the development of insulin resistance and steatosis, the main hallmarks of NAFLD. Considering that estrogen, in particular 17β-estradiol (E2), have been reported to improve mitochondrial biogenesis and function in liver, our aim was to elucidate the role of E2 in preventing fatty acid-induced insulin resistance in hepatocytes through modulation of mitochondrial function, oxidative stress and JNK activation. An in vivo study was conducted in Wistar rats of both sexes (n = 7) fed control diet and high-fat diet (HFD), and in vitro studies were carried out in HepG2 cells treated with palmitate (PA) and E2 for 24 h. Our HFD-fed male rats showed a prediabetic state characterized by greater systemic and hepatic insulin resistance, as well as higher lipid content in liver, compared to females. JNK activation rose markedly in males in response to HFD feeding, in parallel with mitochondrial dysfunction and oxidative stress. Consistently, in PA-exposed HepG2 cells, E2 treatment prevented JNK activation, insulin resistance and fatty acid accumulation. Altogether, our data highlights the importance of E2 as a mitigating factor of fatty acid-insulin resistance in hepatocytes through downregulation of JNK activation, by means of mitochondrial function improvement. |
| DOI: | 10.1016/j.freeradbiomed.2020.02.016 |
| 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 |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | 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 |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D476 | Estradiol | Chemical drug | DB00783 | -- | -- | Under clinical trials | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |