Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases

Shekhawat, Prem; Bennett, Michael J.; Sadovsky, Yoel; Nelson, D. F.; Rakheja, Dinesh; Strauss, Arnold W.

doi:10.1152/ajpendo.00481.2002

Cited by 146 publications

(114 citation statements)

References 41 publications

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“…Most enzymes required for FFA oxidation are highly expressed in the placenta, an organ capable of both transporting fatty acids to the fetus and using them as metabolic fuels (Shekhawat et al 2003). The capacity of releasing glycerol as an index of lipid catabolism in placental explants has previously been reported (Ramsay et al 1991).…”

Section: Ppara In Fetuses and Placentasmentioning

confidence: 99%

Peroxisome proliferator-activated receptor α activation regulates lipid metabolism in the feto-placental unit from diabetic rats

Martínez¹,

Capobianco²,

White³

et al. 2008

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Maternal diabetes promotes an overaccumulation of lipids in the feto-placental unit and impairs feto-placental development and growth. Here, we investigated the role played by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)a in lipid metabolism in fetuses and placentas from control and neonatal streptozotocin-induced diabetic rats. Placentas and fetuses were studied on day 13.5 of gestation. The concentrations of PPARa (by Western blot) and its endogenous agonist leukotriene B 4 (LTB 4 ) (by enzyme immunoassay) were analysed. Placental explants and fetuses were cultured with LTB 4 or clofibrate, and then lipid metabolism analysed (concentrations and synthesis from 14 C-acetate of triglycerides, phospholipids, cholesterol and cholesteryl esters; release of glycerol and free fatty acids (FFAs)).We found that maternal diabetes led to increases in placental concentrations of triglycerides and cholesteryl esters, and fetal concentrations of phospholipids. PPARa agonists downregulated fetal and placental lipid concentrations in control and diabetic rats. The synthesis of lipids was reduced in the diabetic placenta but increased in fetuses from diabetic animals. PPARa agonists reduced the synthesis of lipids in control placenta and in the fetuses from control and diabetic rats. Glycerol and FFA release was enhanced in the diabetic placenta and in control placenta cultured with PPARa agonists. Maternal diabetes led to reductions in fetal and placental LTB 4 concentrations and to increases in placental PPARa concentrations. Overall, these data support a novel role of PPARa as a regulator of lipid metabolism in the fetoplacental unit, relevant in maternal diabetes where fetal and placental PPARa, LTB 4 and lipid concentrations are altered.Reproduction (2008) 136 95-103

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Section: Ppara In Fetuses and Placentasmentioning

confidence: 99%

Peroxisome proliferator-activated receptor α activation regulates lipid metabolism in the feto-placental unit from diabetic rats

Martínez¹,

Capobianco²,

White³

et al. 2008

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“…Therefore, carnitine plays a critical role in the energy metabolism of the tissues that derive substantial portion of their metabolic energy from fatty acid oxidation such as heart, skeletal muscle, liver and placenta [1,2]. Two distinct types of carnitine deficiency states have been identified; primary and secondary.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

Shekhawat

Srinivas

Matern

et al. 2007

Molecular Genetics and Metabolism

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Carnitine is essential for transport of long-chain fatty acids into mitochondria for their subsequent β-oxidation, but its role in the gastrointestinal tract has not been well described. Recently several genetic epidemiologic studies have shown strong association between mutations in carnitine transporter genes OCTN1 and OCTN2 and a propensity to develop Crohn's disease. This study aims to investigate role of carnitine and β-oxidation in the GI tract. We have studied the gastrointestinal tract effects of carnitine deficiency in a mouse model with loss-of-function mutation in the OCTN2 carnitine transporter. juvenile visceral steatosis (OCTN2 -/-) mouse spontaneously develops intestinal villous atrophy, breakdown and inflammation with intense lymphocytic and macrophage infiltration, leading to ulcer formation and gut perforation. There is increased apoptosis of jvs (OCTN2 -/-) gut epithelial cells. We observed an up-regulation of heat shock factor-1 (HSF-1) and several heat shock proteins (HSPs) which are known to regulate OCTN2 gene expression. Intestinal and colonic epithelial cells in wild type mice showed high expression and activity of the enzymes of β-oxidation pathway. These studies provide evidence of an obligatory role for carnitine in the maintenance of normal intestinal and colonic structure and morphology. Fatty acid oxidation, a metabolic pathway regulated by carnitine-dependent entry of long-chain fatty acids into mitochondrial matrix, is likely essential for normal gut function. Our studies suggest that carnitine supplementation, as a means of boosting fatty acid oxidation, may be therapeutically beneficial in patients with inflammation of the intestinal tract.

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“…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).…”

Section: Discussionmentioning

confidence: 61%

“…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). It has also been shown that FAO enzymes are expressed abundantly in human placentas (Shekhawat et al 2003). Furthermore, patients with longchain defects in FAO may already display cardiomyopathy before and immediately after birth (den Boer et al 2003;Olpin et al 2005;Purevsuren et al 2009;Spiekerkoetter et al 2004), demonstrating a role for long-chain FAO during intrauterine life.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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Background: Newborn screening (NBS) for long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency does not discriminate between isolated LCHAD deficiency, isolated long-chain keto acyl-CoA (LCKAT) deficiency and general mitochondrial trifunctional protein (MTP) deficiency. Therefore, screening for LCHAD deficiency inevitably comprises screening for MTP deficiency, which is much less amenable to treatment. Furthermore, absence of a clear classification system for these disorders is still lacking. Materials and Methods:Two newborns screened positive for LCHAD deficiency died at the age of 10 and 31 days, respectively. One due to severe necrotizing enterocolitis (NEC), cardiomyopathy and multiorgan failure and the other due to severe infant respiratory distress syndrome (IRDS) and hypertrophic cardiomyopathy. (Keto)-acylcarnitine concentration and enzymatic analysis of LCHAD and LCKAT suggested MTP deficiency in both patients. Mutation analysis revealed a homozygous HADHB c.357+5delG mutation in one patient and a homozygous splice-site HADHB mutation c.212+1G>C in the other patient.Data on enzymatic and mutation analysis of 40 patients with presumed LCHAD, LCKAT or MTP deficiency were used to design a classification to distinguish between these disorders.Discussion: NEC as presenting symptom in MTP deficiency has not been reported previously. High expression of long-chain fatty acid oxidation enzymes reported in lungs and gut of human foetuses suggests that the severe NEC and IRDS observed in our patients are related to the enzymatic deficiency in these organs during crucial stages of development.Furthermore, as illustrated by the cases we propose a classification system to discriminate LCHAD, LCKAT and MTP deficiency based on enzymatic analysis.

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Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases

Cited by 146 publications

References 41 publications

Peroxisome proliferator-activated receptor α activation regulates lipid metabolism in the feto-placental unit from diabetic rats

Peroxisome proliferator-activated receptor α activation regulates lipid metabolism in the feto-placental unit from diabetic rats

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

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

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