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

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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.

Introduction

Obesity is a growing threat to global health by virtue of its association with a number of cardiovascular risk factors including insulin resistance, hypertension, dyslipidemia and non alcoholic fatty liver disease (NAFLD) [1], [2]. The links between obesity and non-ischaemic heart failure is incompletely understood but, as a general view, cardiac dysfunction, arrhythmias, cardiomyopathy and congestive heart failure occurring in this clinical setting are seldom ascribed to fatty acids overload of cardiac myocytes [1]. The Farnesoid X Receptor (FXR, NR1H4), a nuclear receptor activated by bile acids [3], regulates insulin sensitivity and lipid metabolism. FXR deficiency in mice is associated with the development of pro-atherogenic serum lipoprotein profile [4], while FXR agonism effectively attenuates dyslipidemia, atherosclerosis plaque formation, insulin resistance and NAFLD [5]. A metabolic effect mediated by FXR ligands is the induction of proliferator-activated receptor alpha (PPARα) and pyruvate dehydrogenase kinase-4 (PDK-4) expression, both of which are known to promote fatty acid oxidation [6], [7]. It has been proposed that a downregulation of PPARα and decreased expression of fatty acid β-oxidation enzymes causes intramyocardial lipid accumulation that contribute to the cardiac dysfunction that is sometimes observed with obesity, insulin resistance, and diabetes [8], [9], [10]. This idea was supported by the observation that obese and type 2 diabetic patients with heart failure had a dramatic increase in intramyocardial lipid accumulation, which is attributed to relatively impaired fatty acid β-oxidation due to a reduction in a number of PPARα target gene transcripts [11] as observed in human adult failing heart [12], [13].

However, whether the FXR agonism holds potential for protecting against cardiac lipotoxicity is unknown. In the present study, by using a genetic model of obesity, NAFLD, insulin resistance, hypertension and dyslipidemia, the Zucker obese (fa/fa) rat [14], we demonstrate that FXR activation by a natural, chenodeoxycholic acid (CDCA), and synthetic, GW4064, agonists modulates the expression of genes involved in the lipid β-oxidation in the cardiomyocytes and that chronic administration of CDCA protects against development of myocardiopathy.

Section snippets

Animal protocol

Lean (fa/+) and obese (fa/fa) Zucker rats were purchased from Charles River. Rats were housed on a 12-h light–dark cycle and fed standard laboratory diet ad libitum. All animal experimental procedures were approved by the Animal Study Committee of the University of Perugia. Drug administration was started at 15 weeks of age. In the first set of experiments lean (fa/+) and obese (fa/fa) Zucker rats were treated for 5 days with chenodeoxycholic acid (CDCA) (20 mg/kg orally (O.S.)) and GW4064

Cardiac expression of FXR

In addition to liver and intestine, high levels of FXR mRNA have been detected in the kidney and adrenal glands [3], while low levels of mRNA have been detected in a variety of tissues including mouse and human heart [15], [16] and rat neonatal cardiomyocytes [17]. The expression of FXR in adult obese and lean Zucker rats and neonatal cardiomyocytes was therefore examined by RT-PCR and Western blotting analysis, using liver tissues from fa/fa rats as control (Fig. 1). As shown in Fig. 1A, FXR

Discussion

The obesity-driven lipid ectopic deposition associates with dysfunctional tissues and organs. Islet cell, liver and cardiac manifestations of lipotoxicity include type 2 diabetes, non alcoholic steatohepatitis and dilated cardiomyopathies. Several studies have demonstrated that in the setting of obesity and type 2 diabetes, the heart has a relatively impaired ability to oxidize fat and the accumulation of intramyocardial lipids is associated to reduced heart function [10], [11], [12], [13], [20]

Conflict of interest statement

Authors have no conflict of interest to be disclosed.

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