Intrauterine growth restriction elevates circulating acylcarnitines and suppresses fatty-acid metabolism genes in the fetal sheep heart.

KEY POINTS The fetal heart relies on carbohydrates in utero and must be prepared to metabolize fatty acids after birth but the effects of compromised fetal growth on the maturation of this metabolic system are unknown. Plasma fatty-acylcarnitines are elevated in intrauterine growth restricted (IUGR) fetuses over control fetuses, indicative of impaired fatty acid metabolism in fetal organs. Fatty acid uptake and storage are not different in IUGR cardiomyocytes compared to controls. mRNA levels of genes regulating fatty acid transporter and metabolic enzymes are suppressed in the IUGR myocardium compared to controls, while protein levels remain unchanged. Mismatches in gene and protein expression, and increased circulating fatty acylcarnitines may have long term implications for offspring heart metabolism and adult health in IUGR individuals. This requires further investigation. ABSTRACT At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long chain fatty acylcarnitines compared to controls (C14: CTRL 0.012 ± 0.005 nmol/mL vs IUGR 0.018 ± 0.005 nmol/mL, p<0.05; C18: CTRL 0.027 ± 0.009 nmol/mol vs IUGR 0.043 ± 0.024 nmol/mol, p<0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY-C12 saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), s-oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium (p<0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency. Abstract figure. We investigated to degree to which the cardiac genes that regulate fatty acid metabolism were altered in growth restricted fetuses compared to those that grew normally. As shown by the red arrows, messenger RNA levels for the genes studied were suppressed compared to controls. However, the double headed arrows show that protein levels were unaffected. Circulating long chain fatty acylcarnitines in the fetus were elevated suggesting incomplete metabolism of free fatty acids. Whether these experimental conditions portend adverse outcomes in the postnatal period as the heart transitions to fatty acid metabolism requires further study. This article is protected by copyright. All rights reserved.