Dietary Fat Supply to Failing Hearts Determines Dynamic Lipid Signaling for Nuclear Receptor Activation and Oxidation of Stored Triglyceride

Abstract

Background Intramyocardial triglyceride (TG) turnover is reduced in pressure overloaded, failing hearts, limiting availability of this rich source of long-chain fatty acids (LCFAs) for mitochondrial β-oxidation and nuclear receptor activation. This study explored two major dietary fats, palmitate and oleate, in supporting endogenous TG dynamics and peroxisome proliferator-activated receptor-α (PPAR-α) activation in sham-operated (SHAM) and hypertrophied (transverse aortic constriction, TAC) rat hearts. Methods and Results Isolated SHAM and TAC hearts were provided media containing carbohydrate with either 13C-palmitate or 13C-oleate for dynamic 13C NMR spectroscopy and endpoint LC/MS of TG dynamics. With palmitate, TAC hearts contained 48% less TG versus SHAM (P=0.0003), while oleate maintained elevated TG in TAC, similar to SHAM. TG turnover in TAC was greatly reduced with palmitate (TAC: 46.7±12.2 nmol/g dw/min; SHAM: 84.3±4.9; P=0.0212), as was β-oxidation of TG. Oleate elevated TG turnover in both TAC (140.4±11.2) and SHAM (143.9±15.6), restoring TG oxidation in TAC. PPAR-α target gene transcripts were reduced by 70% in TAC with palmitate, while oleate induced normal transcript levels. Additionally, mRNA levels for PGC-1α and PGC-1β in TAC hearts were maintained by oleate. With these metabolic effects, oleate also supported a 25% improvement in contractility over palmitate with TAC (P=0.0202). Conclusions The findings link reduced intracellular lipid storage dynamics to impaired PPAR-α signaling and contractility in diseased hearts, consistent with a rate-dependent lipolytic activation of PPAR-α. In decompensated hearts, oleate may serve as a beneficial energy substrate versus palmitate by upregulating TG dynamics and nuclear receptor signaling.

Cardiac metabolism — A promising therapeutic target for heart failure

“…Levels of toxic lipid intermediates have also been shown to be increased in rats subjected to TAC (Lahey, et al, 2014). The same group also identified that TAG turnover rate is also of critical importance in HF, rather than simply content, and normalizing TAG turnover rate via supplementation with the dietary FA oleate led to improved FA metabolism and contractile function in TAC rats (Lahey, et al, 2014).…”

“…The falling levels of long chain free FA from this altered TAG turnover lead to reduced signaling via the PPARα pathway (as long chain free FA is an important ligand for PPARα activation; Lahey, et al, 2014). O'Donnell et al (2008) observed a significant reduction in TAG content and turnover in rats subjected to pressure-overload HF, due to an upregulation in the TAG hydrolase, and adipose triglyceride lipase enzyme (O'Donnell, et al, 2008).…”

“…A reduction in TAG content and increased levels of toxic lipid intermediates were also found in patients with chronic HF, and this was successfully corrected following mechanical unloading with left ventricular assist device (LVAD) therapy (Chokshi, et al, 2012). Levels of toxic lipid intermediates have also been shown to be increased in rats subjected to TAC (Lahey, et al, 2014). The same group also identified that TAG turnover rate is also of critical importance in HF, rather than simply content, and normalizing TAG turnover rate via supplementation with the dietary FA oleate led to improved FA metabolism and contractile function in TAC rats (Lahey, et al, 2014).…”

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

“…Despite having a different etiology, late-stage heart failure is commonly characterized by severe changes in myocardial substrate metabolism, with a switch from fatty acid oxidation toward predominant glycolysis (4 -6). Conflicting evidence exists as to whether this substrate switch is beneficial or detrimental (7), but several previous studies have indicated that an increased availability of lipid substrates that counteract the substrate switch could improve cardiac function (7,8). Moreover, treatment options, which improve substrate availability, are attractive because the failing heart is often considered to be "an engine running out of fuel" (9).…”

Seven-Day Caloric and Saturated Fat Restriction Increases Myocardial Dietary Fatty Acid Partitioning in Impaired Glucose-Tolerant Subjects

“…In subjects with type 2 diabetes, a 3-day very lowcalorie diet (471 kcal/day, but with SFA .13%) induced an increase in myocardial TG levels and reduced diastolic function, but with no change in LVEF measured by MRI (41). Fatty acid uptake by the heart is essential for intramyocellular TG repletion and the maintenance of cardiac function (42,43). It is therefore premature to postulate that enhanced cardiac DFA partitioning can be mechanistically linked to a reduction in LVEF in the current study.…”