PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis

Abstract

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara^-/-) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara^-/- mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara^-/- mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara^-/- mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality.

New & noteworthy: In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.

Keywords: PPARα; cardiovascular failure; sepsis; septic shock.

Fig. 1.

Echocardiographic evaluation of in vivo heart function. A: cecal ligation and puncture sepsis model (CLP) cohort, n = 16 per genotype; B: sham cohort, n = 8–9 per genotype (diameters normalized to body weight; *P < 0.05 WT vs. Ppara^−/− at that time point, †P < 0.05 WT vs. baseline, ‡P < 0.05 Ppara^−/− vs. baseline).

Fig. 2.

Ex vivo evaluation of heart function (n = 8–9 per group; *P < 0.05).

Fig. 3.

Myocardial substrate utilization in sepsis. A: substrate fractional contribution to citric acid cycle (CAC); B: substrate flux through CAC (n = 8–9 per group; *P < 0.05).

Fig. 4.

In vivo cardiac tissue triglyceride levels (n = 6–7 per group; *P < 0.05; an interaction effect was observed between genotype and condition on two-factor ANOVA analysis).

Fig. 5.

In vivo protein expression and phosphorylation states of regulators of pyruvate incorporation into CAC and fatty acid oxidation (FAO) (n = 3–4 per group; *P < 0.05). PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; ACC, total acetyl-CoA carboxylase; MCD, malonyl CoA-decarboxylase.

Fig. 6.

Whole blood glucose and serum substrate levels (n = 9–16 per group; *P < 0.05; interaction effects between genotype and condition were observed on two-factor ANOVA analysis for lactate and ketone substrates). NEFA, nonesterified fatty acid; TG, triglyceride.

Fig. 7.

Electron micrographs of myocardium after CLP. *Areas of contractile apparatus degeneration. Mitochondria identified with arrowheads on ×50,000 panels (n = 3–4 per group).