Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1α-HO-1-PGC1α-mitochondrial signaling
| Autor: | Raffaele, M., Bellner, L., Singh, S. P., Favero, G., Rezzani, R., Rodella, L. F., Falck, J. R., Abraham, N. G., Vanella, L. |
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| Rok vydání: | 2019 |
| Předmět: |
CYP-450 epoxygenase
Insulin sensitivity Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Non-alcoholic fatty liver disease (NAFLD) Fatty Liver Disease Models Animal Mice FGF21 SIRT1 8 11 14-Eicosatrienoic Acid Non-alcoholic Fatty Liver Disease Animals Receptors Leptin Heme Oxygenase-1 Signal Transduction |
| Zdroj: | Experimental cell research. 380(2) |
| ISSN: | 1090-2422 |
| Popis: | Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD.We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks.db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration.EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD. |
| Databáze: | OpenAIRE |
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