FXR activation improves myocardial fatty acid metabolism in a rodent model of obesity-driven cardiotoxicity

Abstract 

Background and aims

Obesity-driven lipotoxicity is a risk factors for cardiovascular disease. The Farnesoid X Receptor (FXR) is a bile acids sensor and member of the nuclear receptor superfamily. Activation of FXR lowers plasma triacylglycerols and glucose levels through a mechanism that involves both the repression of key regulatory genes in the liver and the modulation of insulin sensitivity in peripheral tissues. In the present study we have investigated whether administering obese (fa/fa) Zucker rats, a genetic model of obesity associated with dyslipidemia and insulin resistance, with an FXR ligand protects against lipid-induced cardiomyopathy.

Methods and results

FXR is expressed in neonatal cardiomyocytes and the treatment with FXR agonists, chenodeoxycholic acid (CDCA), and GW4064, increased the mRNA expression of FXR and its canonical target gene, the small heterodimer partner (SHP), as well as proliferator-activated receptor alpha PPARα, acyl-CoA oxidase (AOX) and pyruvate dehydrogenase kinase (PDK-4). Feeding obese fa/fa rats with CDCA, 12 weeks, reduced hyperinsulinemia and hyperlipidaemia. The histological–pathological analysis of hearts demonstrated that treatment with the FXR ligand reduced lipid heart content decreased the rate of apoptosis, fibrosis scores and restored heart insulin signalling. Chronic CDCA administration, in the heart, induced PPARα and PPARα-regulated genes involved in β-oxidation.

Conclusion

FXR agonism exerts beneficial effects in a genetic model of lipid-induced cardiomyopathy. The striking benefit of this therapy on cardiac function in this model warrants an effort to determine whether a counterpart of this activity translates in human settings.

Keywords: Farnesoid X Receptor (FXR), Cardiomyopathy, Chenodeoxycholic acid (CDCA), Heart metabolism

Abbreviations: AOX, acyl-CoA oxidase, AKT, serine/threonine protein kinase PKB, BA, bile acid, CDCA, chenodeoxycholic acid, CD36, fatty acid Translocase, Coll α-1, collagen type I, CPT-1, carnitine palmitoyltransferase 1, DAPI, 4’,6-diamidino-2-phenylindole, FA, fatty acid, FABP-3, fatty acid binding protein 3, FAS, fatty acid synthase, FXR, Farnesoid X Receptor, GLUT4, glucose transporter 4, G6Pase, glucose-6-phosphatase, H&E, haematoxylin–eosin, MCD, malonyl-CoA decarboxylase, MHC α, myosin heavy chain α, MHC β, myosin heavy chain β, NAFLD, non alcoholic fatty liver disease, NEFA, nonesterified fatty acids, PDK-4, pyruvate dehydrogenase kinase-4, PPARα, peroxisome proliferator – activated receptor-α, PPARγ, peroxisome proliferator – activated receptor-γ, ROS, reactive oxygen species, RT-PCR, reverse transcription polymerase chain reaction, SHP, small heterodimer partner, TGF-β1, transforming growth factor 1, TNFα, tumour necrosis factor α, TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling, UCP-3, uncoupling protein 3