The Fetalto Adult Energy Metabolic Switch Postnatal Induction of Cellular Mitochondrial Energy Transduction Production Pathways

Following birth, the heart undergoes a remarkable metabolic maturation such that the normal adult myocardium is capable of high-capacity utilization of both glucose and fatty acids for ATP production (Bing 1955; Neely et al. 1972; Warshaw 1972). During the fetal stages, the heart relies mainly on glucose for energy. Following birth, the increased hemodynamic demands imposed on the left ventricle, which serves as a constant pump throughout the life of the organism, mandates a reliable, high-capacity energy production system. The increased postnatal energy demands are met largely through the rapid proliferation of mitochondria and coor

Cordio Vascuiar System Indction

Figure 1. The balance of myocardial energy substrate utilization in the normal and diseased heart. The normal adult heart derives ~50-70% of its energy from the oxidation of FA. However, during fetal stages and in pathologic cardiac hypertrophy and hypoxic conditions, the heart relies mainly on glycolysis to produce ATP. Conversely, following a fast or in the uncontrolled diabetic state, over 90% of energy produced in the heart is derived from FAO.

Figure 1. The balance of myocardial energy substrate utilization in the normal and diseased heart. The normal adult heart derives ~50-70% of its energy from the oxidation of FA. However, during fetal stages and in pathologic cardiac hypertrophy and hypoxic conditions, the heart relies mainly on glycolysis to produce ATP. Conversely, following a fast or in the uncontrolled diabetic state, over 90% of energy produced in the heart is derived from FAO.

dinate induction of the expression of nuclear genes encoding a variety of mitochondrial enzymes, including those of the FAO pathway (Kelly et al. 1989; Nagao et al. 1993). The postnatal mammalian diet, which is rich in milk fat, provides a new source of fatty acid substrate. In addition, the expression of proteins involved in fatty acid import such as fatty acid transport protein and FAT/CD36 are induced in heart following birth. Collectively, these developmentally programmed events lead to a switch from glucose to fatty acids as the chief myocardial energy substrate.

The perinatal switch in myocardial energy substrate preference is considered to be adaptive for several reasons. First, per mole of substrate, fatty acids provide a much greater yield of ATP compared to glucose, albeit at a higher oxygen consumption cost. Second, the mammalian diet provides an ample quantity of fatty acids to serve as a substrate source. Third, as noted above, the energy metabolic maturation of the postnatal heart provides flexibility in substrate preference. Specifically, in postprandial states and certain pathologic conditions, including ischemia or hypertrophy, glucose re-emerges as the chief substrate for energy production. The balanced use of fatty acids and glucose provides an energy substrate reserve that protects the heart from periods of mismatch between energy demands and production.

The Mitochondrial FAO Pathway as a Focus for the Characterization of Gene Regulatory Pathways Involved in the Cardiac Metabolic Maturation Program

The postnatal myocardial metabolic switch is associated with a dramatic induction in the expression of nuclear genes involved in the uptake and oxidation of fatty acids (Fig. 2A) (Kelly et al. 1989; Nagao et al. 1993). Following birth, the increase in FAO enzyme gene expression occurs in parallel with a marked increase in cellular mitochondrial volume density (mitochondrial biogene sis) (Fig. 2B). Two mitochondrial FAO enzyme genes have been used as a starting point to delineate the upstream transcriptional regulatory events involved in the cardiac energy metabolic maturation program. The first, muscle carnitine palmitoyltransferase I (M-CPT I), catalyzes a tightly regulated, rate-limiting step in the mito-chondrial import of long-chain fatty acids (see Fig. 2A). The second, medium-chain acyl-CoA dehydrogenase (MCAD), catalyzes the initial step within the FAO spiral (Fig. 2A) and is the most commonly deficient enzyme among the human inborn errors of FAO. The levels of mRNA encoding MCAD (Fig. 2B) and M-CPT I parallel the developmental switch in energy substrate utilization in the rodent heart (Kelly et al. 1989; Lehman et al. 2000). The expression of the MCAD and M-CPT I genes is also coordinately increased in dietary and physiologic conditions known to increase cardiac and skeletal muscle FAO rates such as short-term fasting (Nagao et al. 1993; Leone et al. 1999) and chronic stimulation of muscle (Cresci et al. 1996).

The postnatal induction of MCAD and M-CPT I gene expression in the developing heart provided proof of concept that these genes were targets for upstream regulatory pathways involved in the transcriptional control of my-ocardial energy metabolism. The initial approach involved mapping the cis-acting regulatory elements within the promoter regions of these genes. Two complementary experimental strategies were employed. First, gene promoter regulatory regions involved in the cardiac developmental control of MCAD gene expression were mapped in vivo in promoter-reporter transgenic mice (Disch et al. 1996). Second, relevant M-CPT I and MCAD gene promoter elements were defined in rat neonatal cardiac my-ocytes in culture (Disch et al. 1996; Brandt et al. 1998). The latter approach revealed that fatty acid substrate activated the transcription of the FAO enzyme genes. Both strategies demonstrated that DNA sequences containing recognition sites for members of the nuclear hormone receptor superfamily were necessary for developmental and fatty acid-mediated control of MCAD and M-CPT I gene

Figure 2. (A) The cellular fatty acid oxidation (FAO) pathway. The diagram depicts the major routes of fatty acid uptake and oxidation in the cardiac myocyte. Abbreviations: (VLDL) very low density lipoproteins; (NEFA) non-esterified fatty acids; (FATP) fatty acid transport protein; (ACS) acyl-CoA synthetase; (CPT I) carnitine palmitoyl-transferase I; (CPT II) carnitine palmitoyltrans-ferase II; (1) very long-chain (VLCAD), long-chain (LCAD), and medium-chain (MCAD) acyl-CoA dehydrogenases; (2) enoyl-CoA hydratase; (3) 3-hydroxyacyl-CoA dehydrogenase; (4) 3-ketoacyl-CoA thiolase. The asterisks denote known PPARa target genes. (B) Developmental shifts in cardiac energy substrate preference and FAO enzyme gene expression. (Top) The fetal heart relies primarily on anaerobic glucose utilization pathways. Following birth, the heart increases its capacity for and dependence on the oxidation of fatty acids to produce ATP. The normal adult mammalian heart relies principally on FA for energy production. The changes in myocardial substrate preference following birth are associated with robust mitochondrial biogenesis and increased expression of genes encoding FAO enzymes. (Bottom) A representative autoradiograph of a Northern blot analysis demonstrating the developmental regulation of the nuclear gene encoding the mitochondrial FAO enzyme MCAD (PD1 = postnatal day 1).

Plasma Membrane

Cytosol

Outer Mitochondrial Membrane

Inner Mitochondrial Membrane

Mitochondrial Matrix

VLDL » long-chain fatty acids NEFA/Albumin _¿f_

VLDL » long-chain fatty acids NEFA/Albumin _¿f_

Cytosol

Outer Mitochondrial Membrane

Inner Mitochondrial Membrane

Mitochondrial Matrix

Fetal Heart

Glucose

Postnatal Heart

Mitochondrial biogenesis and increased expression of FAO enzymes

Adult Heart

Fatty Acids

Glucose

Fetal

PD 1

Adult

MCAD Gene Expression expression. These observations led to the discovery that the fatty acid-activated nuclear receptor transcription factor, PPARa, and its heterodimeric partner, RXR, serve as critical components of the postnatal control of mitochon-drial FAO enzyme gene expression in heart.

PPARa: A Critical Transcriptional Regulator of Cardiac Lipid Utilization Pathways

PPARa was originally identified by its involvement in the hepatic peroxisomal proliferative response to fibrates (Issemann and Green 1990). Subsequently, two other members of the PPAR family were identified (PPARß/ö and PPARy) (for review, see Desvergne and Wahli 1999). The results of studies by a large number of laboratories have shown that PPARa and y serve distinct but critical roles in the control of lipid metabolism and other biologic processes. The functional role of PPARß remains unclear. PPARs regulate the transcription of target genes by binding their target DNA regulatory elements as a het-erodimer with the retinoid X receptor (RXR). PPARa, a focus of this review, is enriched in tissues with high capacity for FAO, including liver and heart, and activates cellular lipid utilization pathways. PPARy, which is adipose-enriched, plays a critical role in the differentiation and function of the adipocyte; a lipid storage cell. Importantly, the activity of the PPARs is ligand-dependent. A variety of activating ligands for the PPARs have been identified, most of which are long-chain fatty acids or their derivatives, although certain prostaglandin derivatives can also serve to activate the PPARs (Xu et al. 1999). The endogenous ligands for the PPARs have not been identified with certainty. Of interest is that certain activators are PPAR-specific. For example, thiazolidine-diones, a new class of insulin-sensitizing drugs, are PPARy-specific activators, whereas fibrates (hypolipidemic drugs) are more specific for PPARa (Xu et al. 1999). The existence of PPAR-specific activators has generated an intense interest in the development of drugs that have customized metabolic effects by virtue of the fact that PPARa and y have distinct tissue expression patterns and generally opposing effects on lipid metabolism.

It is now known that PPARa activates the expression of cardiac genes involved in multiple FA utilization pathways including lipid uptake, thioesterification, and peroxisomal and mitochondrial FAO (see Fig. 2A) (for review, see Barger and Kelly 2000). Studies of mice null for PPARa (PPARa-/-) have shown that the basal expression of mitochondrial and peroxisomal FAO enzymes in liver and heart is reduced (Lee et al. 1995; Aoyama et al. 1998; Djouadi et al. 1998). The PPARa-/-mice, which were produced by the Gonzalez laboratory (Lee et al. 1995), appear normal under basal physiologic conditions. Studies of the isolated working PPARa-/-heart have shown that FAO rates are markedly diminished, whereas glucose utilization is increased similar to that of the fetal heart (Campbell et al. 2002). PPARa-/-mice are unable to appropriately increase the expression of target genes involved in myocardial or hepatic FA utilization in response to physiologic or dietary demands known to increase FAO rates, such as fasting (Kersten et al. 1999; Leone et al. 1999). Gain-of-function studies performed by our group have also demonstrated the importance of PPARa in the control of cellular FA utilization pathways. Cardiac-specific overexpression of PPARa results in increased myocardial FAO enzyme expression and palmitate oxidation rates (Finck et al. 2002). Collectively, these studies have shown that PPARa plays a critical role in the developmental and physiologic control of cardiac FA utilization pathways.

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