Obeticholic acid protects against diabetic cardiomyopathy by activation of FXR/Nrf2 signaling in db/db mice

摘要

Diabetic cardiomyopathy (DCM) is one of the major cardiac complications in diabetic patients and a major reason for the death of diabetic patients. Obeticholic acid (OCA) is a semi-synthetic bile acid analogue. The objective of the present study was to investigate the possible cardio-protective effect of OCA against DCM. db/db diabetic mice were given OCA with or without injection of LV-short hairpin farnesoid X receptor (shFXR), and general glucose and lipid metabolism, myocardial morphology and function, myocardial fibrosis, inflammation and oxidative stress were evaluated. We found that OCA significantly ameliorated metabolic dysfunctions. Moreover, OCA attenuated morphological injury of cardiac tissue, restored the abnormal changes of hemodynamic variables and echocardiographic parameters. The Sirius-Red staining of cardiac tissue and mRNA expression of fibrotic biomarkers, including connective tissue growth factor, osteopontin, Transforming growth factor-beta 1, atrial natriuretic peptide, Collagen I, and Collagen III were decreased by OCA. Systemic levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6 were reduced by OCA. Moreover, OCA decreased oxidant products and increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and the expression and activities of antioxidant enzymes. Injection of LV-shFXR downregulated FXR expression and inhibited all these beneficial effects of OCA. FXR is major target that mediated that beneficial effect of OCA. In summary, FXR/Nrf2 signaling was involved in OCA-induced amelioration of metabolic disorder, oxidative stress, inflammation, fibrosis and myocardial dysfunction. Our findings provide new evidence for the interaction of FXR and Nrf2 signaling and novel option for the intervention of DCM.