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L-Carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter [ATB.sup.0,+]. Loss-of-function mutations in OCTN2 may be associated with inflammatory bowel disease (IBD), suggesting a role for carnitine in intestinal/colonic health. In contrast, [ATB.sup.0,+] is upregulated in bowel inflammation. Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. Butyryl-L-carnitine (BC), a butyrate ester of carnitine, may have potential for treatment of gut inflammation, since BC would supply both butyrate and carnitine. We examined the transport of BC via [ATB.sup.0,+] to determine if this transporter could serve as a delivery system for BC. We also examined the transport of BC via OCTN2. Studies were done with cloned [ATB.sup.0, +] and OCTN2 in heterologous expression systems. BC inhibited [ATB.sup.0,+]-mediated glycine transport in mammalian cells ([IC.sub.50], 4.6 [+ or -] 0.7 mM). In Xenopus laevis oocytes expressing human [ATB.sup.0,+], BC induced [Na.sup.+]-dependent inward currents under voltage-clamp conditions. The currents were saturable with a [K.sub.0.5] of 1.4 [+ or -] 0.1 mM. [Na.sup.+] activation kinetics of BC-induced currents suggested involvement of two [Na.sup.+] per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake ([IC.sub.50, 1.5 [+ or -] 0.3 [micro]M). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were [Na.sup.+] dependent and saturable ([K.sub.0.5], 0.40 [+ or -] 0.02 [micro]M). We conclude that [ATB.sup.0,+] is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. [ATB.sup.0,+] may mediate intestinal absorption of BC when OCTN2 is defective. butyryl-L-carnitine; OCTN2; [ATB.sup.0,+]; carnitine; butyrate; Crohn's disease; necrotizing enterocolitis

The role of fat metabolism during human pregnancy and in placental growth and function is poorly understood. Mitochondrial fatty acid oxidation disorders in an affected fetus are associated with maternal diseases of pregnancy, including preeclampsia, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelets syndrome called HELLP. We have investigated the developmental expression and activity of six fatty acid [beta]-oxidation enzymes at various gestational-age human placentas. Placental specimens exhibited abundant expression of all six enzymes, as assessed by immunohistochemical and immunoblot analyses, with greater staining in syncytiotrophoblasts compared with other placental cell types. [beta]-Oxidation enzyme activities in placental tissues were higher early in gestation and lower near term. Trophoblast cells in culture oxidized tritium-labeled palmitate and myristate in substantial amounts, indicating that the human placenta utilizes fatty acids as a significant metabolic fuel. Thus human placenta derives energy from fatty acid oxidation, providing a potential explanation for the association of fetal fatty acid oxidation disorders with maternal liver diseases in pregnancy. acute fatty liver of pregnancy; mitochondria; hemolysis, elevated liver enzymes, and low platelets syndrome

Objective: Assessment of adrenal function in a sick neonate remains a challenge in spite of major advances in neonatal care. We used 2D ultrasound of adrenal glands to assess maturity of adrenal glands in extremely preterm infants and sick term and near term infants.Study Design: We collected demographics details of 99 mother-infants pairs (24-41 weeks) and obtained 2D ultrasound scans of adrenal glands in first week of life to measure adrenal volume, fetal zone size, and adrenal to kidney ratios. Relationship between adrenal measurements, antenatal factors, and postnatal outcomes were studied.Results: We reported normative adrenal gland volume data during gestation from 80 appropriate for gestational age (AGA) infants. In a binary analysis, adrenal size was significantly related to gender, race, intrauterine growth restriction (IUGR), maternal chorioamnionitis, and maternal hypertension. Linear regression analysis showed that fetal zone is significantly related to not only gestational age but also chorioamnionitis and later development of intraventricular hemorrhage (IVH). Adrenal volume likewise is also related to gestational age, preeclampsia, and IVH.Conclusions: Antenatal maternal factors and uterine environment affects adrenal growth and development thus postnatal high resolution 2D US scan of adrenal glands can provide useful information to predict outcomes. This information can complement hormone and adrenocorticotrophic hormone (ACTH) stimulation assays. [ABSTRACT FROM AUTHOR]

We have investigated the gross, microscopic and molecular effects of carnitine deficiency in the neonatal gut using a mouse model with a loss-of-function mutation in the OCTN2 (SLC22A5) carnitine transporter. The tissue carnitine content of neonatal homozygous (OCTN2-/-) mouse small intestine was markedly reduced; the intestine displayed signs of stunted villous growth, early signs of inflammation, lymphocytic and macrophage infiltration and villous structure breakdown. Mitochondrial b-oxidation was active throughout the GI tract in wild type newborn mice as seen by expression of 6 key enzymes involved in b-oxidation of fatty acids and genes for these 6 enzymes were up-regulated in OCTN2-/- mice. There was increased apoptosis in gut samples from OCTN2-/- mice. OCTN2-/- mice developed a severe immune phenotype, where the thymus, spleen and lymph nodes became atrophied secondary to increased apoptosis. Carnitine deficiency led to increased expression of CD45-B220+ lymphocytes with increased production of basal and anti-CD3-stimulated pro-inflammatory cytokines in immune cells. Real-time PCR array analysis in OCTN2-/- mouse gut epithelium demonstrated down-regulation of TGF-β/BMP pathway genes. We conclude that carnitine plays a major role in neonatal OCTN2-/- mouse gut development and differentiation, and that severe carnitine deficiency leads to increased apoptosis of enterocytes, villous atrophy, inflammation and gut injury. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

L-Carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter ATB°,+ Loss-of-function mutations in OCTN2 may be associated with inflammatory bowel disease (IBD), suggesting a role for camitine in intestinal/colonic health. In contrast, ATB°,+ is upregulated in bowel inflammation. Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. Butyryl-L-carnitine (BC), a butyrate ester of carnitine, may have potential for treatment of gut inflammation, since BC would supply both butyrate and camitine. We examined the transport of BC via ATB°,+to determine if this transporter could serve as a delivery system for BC. We also examined the transport of BC via OCTN2. Studies were done with cloned ATB°,+ and OCTN2 in heterologous expression systems. BC inhibited ATB°,+-mediated glycine transport in mammalian cells (IC50, 4.6 ± 0.7 mM). In Xenopus laevis oocytes expressing human ATB°,+ BC induced Na+-dependent inward currents under voltage-clamp conditions. The currents were saturable with a K0.5 of 1.4 ± 0.1 mM. Na+ activation kinetics of BC-induced currents suggested involvement of two Na+ per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake (IC50, 1.5 ± 0.3 μM). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were Na+ dependent and saturable (K0.5, 0.40 ± 0.02 μM). We conclude that ATB°,+ is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. ATB°,+ may mediate intestinal absorption of BC when OCTN2 is defective. [ABSTRACT FROM AUTHOR]