Protective effect of obeticholic acid on obesity-induced cardiomyopathy

[GW30-e0060]

Authors: Chao Li^1,2, Shijun Zhang³, Zhibo Gai^1,2, Yunlun Li¹

¹Shandong University of Traditional Chinese Medicine

²Department of Clinical Pharmacology and Toxicology, University Hospital of Zurich

³Shandong University of Traditional Chinese Medicine, Jinan, China

OBJECTIVES Obesity is a major contributor to myocardial cell apoptosis, fibrosis and ventricle hypertrophy, and associated with the increased risk of hypertrophic cardiomyopathy. Obeticholic acid (OCA), a farnesoid X receptor agonist, is a key regulator of lipid metabolism, inflammatory, fibrosis and metabolic pathways. This study was performed to investigate the effect and mechanism of OCA on obesity-induced myocardial injury.

METHODS C57Bl/6 mice were fed with a 45% high fat diet (HFD) or a standard diet. Biochemical parameters and myocardial pathological changes were examined. Energy metabolism in isolated working heart using radioactive was also tested to reveal the mechanism of myocardial injury. In vitro, 3D cell culture, mitochondria damage and ATP production of C2C12 cells cultured with palmitic acid (PA) in the absence or presence of OCA were tested.

RESULTS The body weight of HFD C57Bl/6 mice has increased by 22.7% compared with mice fed with normal diet. In addition, HFD-induced obese mice developed cardiac hypertrophy, fibrosis, inflammation, apoptosis, oxidative injury, which was rescued by OCA treatment. There was also a remarkably mitochondria damage in the obese mice and OCA prevented against the mitochondria damage. In vitro, 3D cell culture showed that PA reduced the myocardial contraction and viability. PA also increased the apoptosis rate of C2C12 cells and induced mitochondrial damage identified by the Tom20 level and ATP production assay. OCA showed a protective effect against PA-induced mitochondrial damage and myocardial damage. The results of energy metabolism in isolated working heart further indicated that the contribution of glucose oxidation to ATP production is lower than palmitate oxidation in HFD-induced obese mice heart, and OCA promoted glucose oxidation to protect against PA-induced mitochondrial damage.

CONCLUSIONS The present data suggested that OCA reduced the myocardial cell apoptosis, fibrosis and inflammation in the HFD-induced obese C57Bl/6 mice. OCA also protected cardiomyocytes against PA-induced mitochondria damage through promoting glucose oxidation. Our findings provide evidence for the protective role of OCA in myocardial cells.