Fatty acid oxidation in the human fetus: Implications for fetal and adult disease

Abstract

Studies in the last few years have shown a remarkably high activity of fatty acid oxidation (FAO) enzymes in human placenta. We have recently shown mRNA expression as well as enzymatic activity of long-chain FAO enzymes in the human embryo and fetus. In this study we show activity of the FAO enzymes carnitine palmitoyltranferase 1, medium-chain acyl-CoA dehydrogenase and short-chain hydroxyacyl-CoA dehydrogenase in embryonic and fetal tissues. In addition, we show the presence of different acylcarnitines in fetal liver and kidney, which substantiates the notion that the mitochondrial FAO enzymes are not only present in human fetal tissues but also metabolically active. In a glucose-rich environment FAO might be necessary for additional ATP production from fatty acids, but also for the breakdown of fatty acids that are products of the turnover of membranes in the growing fetus. The importance of FAO in the human embryo and fetus is further stressed by the fact that a higher frequency of prematurity, intrauterine growth retardation, fetal morbidity and intrauterine death is noted in long-chain FAO defects. Furthermore, in animal studies, gestational loss during early embryonic development has been observed as a consequence of disturbed FAO. Finally, there are indications that regulation of activity of FAO during fetal development might not only be important for fetal life but may also have implications for health and disease in adulthood.

Clinical and biochemical improvement of very long-chain acyl-CoA dehydrogenase deficiency in pregnancy

“…Furthermore, studies on fetal tissues, such as the liver and heart, showed strong expression and enzyme activity of VLCAD and other FA oxidation enzymes, emphasizing the role of b-oxidation during early human development. 13,14 This beneficial effect of the placento-maternal metabolic interactions was observed in our patient, as evidenced by improvement of her acylcarnitine profiles in the second and third trimester (Figure 1). This observation also suggests that the toxicity of the accumulated acylcarnitine moieties has a more significant role in eliciting the myopathic manifestations than the energy deficits associated with underutilization of FAs.…”

“…3,7 On the basis of our patient's clinical profile of adult-onset myopathic form of VLCAD deficiency and her history of unprovoked recurrent rhabdomyolysis, we had significant concerns regarding her ability to tolerate any acute intrapartum changes in the metabolic demands. However, given the potential substitutive function of the placental and fetal b-oxidation, 8 we predicted that the mother could experience improvement in her biochemical phenotype. The patient's myalgia and muscle weakness temporally dissipated antepartum with noted significant nadirs of her biochemical markers in the second trimester and completely normalized in latter stages of gestation (Figure 1).…”

“…The patient was also counseled regarding the theoretical possibility of developing acute fatty liver of pregnancy and hemolysis, elevated liver enzymes and low platelets syndrome, as these pathologies have been seen in other FA b-oxidation disorders. 8,9 Her prenatal laboratories and fetal sonographic examination in midgestation were unremarkable. Maternal serum acylcarnitine profile (Figure 1), liver enzymes, urine organic acids and plasma CK levels were followed up the throughout pregnancy.…”

“…In addition, maternal triglyceride levels rise two-to threefold during the catabolic latter third of gestation, thereby increasing the need for FAs uptake and metabolism. However, as the human placenta expresses the enzymes involved in the FA b-oxidation in levels similar or higher to those seen in normal liver, 8 an affected mother carrying an unaffected fetus might improve clinically as the placental mass grows and enables efficient FA oxidation. Lipoprotein lipase, an enzyme that hydrolyzes plasma triacylglycerol, is highly expressed on the maternal surface of the placenta.…”

Necrotizing Enterocolitis and Respiratory Distress Syndrome as First Clinical Presentation of Mitochondrial Trifunctional Protein Deficiency

“…Although it is generally assumed that FAO plays no or only a minor role during intrauterine life due to the abundance of glucose provided by the mother via the placenta (Oey et al 2006;Shekhawat et al 2003), the clinical course in our patients, as well as the patient with isolated LCKAT deficiency described by Das et al (2006), suggests that normal function of the MTP complex is needed for normal intestinal and pulmonary development and function. Berger and Wood showed that complete disruption of long-chain FAO at the level of LCAD in animal models results in increased embryonic mortality (Berger and Wood 2004).…”