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