Effect of neonatal hypoxia on the development of hepatic lipase in the rat

Lee, Ping C.; Jelinek, B. H.; Struve, Mark; Bruder, Eric D.; Raff, Hershel

doi:10.1152/ajpregu.2000.279.4.r1341

Cited by 21 publications

(22 citation statements)

References 29 publications

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“…We and others have previously shown that hypoxia in neonates leads to increased serum TG concentrations (9,12,18,20,29). Hypoxia may modulate the function of enzymes associated with TG synthesis and degradation (12,38).…”

Section: Discussionmentioning

confidence: 97%

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Bruder

Lee²,

Raff³

2005

Journal of Applied Physiology

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treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids. J Appl Physiol 98: [981][982][983][984][985][986][987][988][989][990] 2005. First published November 12, 2004; doi:10.1152/japplphysiol.01029.2004.-Dexamethasone is used as treatment for a variety of neonatal syndromes, including respiratory distress. The present study utilized the power of comprehensive lipid profiling to characterize changes in lipid metabolism in the neonatal lung and brain associated with dexamethasone treatment and also determined the interaction of dexamethasone with hypoxia. A 4-day tapering-dose regimen of dexamethasone was administered at 0800 on postnatal days 3 (0.5 mg/kg), 4 (0.25 mg/kg), 5 (0.125 mg/kg), and 6 (0.05 mg/kg). A subgroup of rats was exposed to hypoxia from birth to 7 days of age. Dexamethasone treatment elicited numerous specific changes in the lipid profile of the normoxic lung, such as increased concentrations of saturated fatty acids in the phosphatidylcholine and cholesterol ester classes. These increases were more profound in the lungs of hypoxic pups. Additional increases in cardiolipin concentrations were also measured in lungs of hypoxic pups treated with dexamethasone. We measured widespread increases in serum lipids after dexamethasone treatment, but the effects were not equivalent between normoxic and hypoxic pups. Dexamethasone treatment in hypoxic pups increased 20:4n6 and 22:6n3 concentrations in the free fatty acid class of the brain. Our results suggest that dexamethasone treatment in neonates elicits specific changes in lung lipid metabolism associated with surfactant production, independent of changes in serum lipids. These findings illustrate the benefits of dexamethasone on lung function but also raise the potential for negative effects due to hyperlipidemia and subtle changes in brain lipid metabolism. hypoxia; glucocorticoid therapy; neonate INHALED AND SYSTEMIC GLUCOCORTICOIDS have been widely used to treat syndromes of perinatal distress, many of which have an inflammatory component requiring pharmacological therapy (3,7,23,25,53). Dexamethasone, a highly potent glucocorticoid, has been the treatment of choice for neonates who are hypoxic due to cardiopulmonary conditions such as bronchopulmonary dysplasia (2,13,33,46,50). A major motivation for this therapy is the promotion of surfactant production and lung maturation and to induce closure of the ductus arteriosus (6,34,43,45,47). Dexamethasone decreases the duration of ventilatory support and lowers the incidence of chronic lung disease (13,23,33,50).Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2). It is for these reasons that the use of dexamethasone in neonates is decreasing (39) and...

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Section: Discussionmentioning

confidence: 97%

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Bruder

Lee²,

Raff³

2005

Journal of Applied Physiology

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“…It has been hypothesized that this period, characterized by diminished adrenal sensitivity to ACTH, allows for normal brain development by keeping plasma glucocorticoid concentrations at a steady level (33). Neonatal hypoxia also causes shifts in intermediary metabolism, including hyperlipidemia and fatty liver (2,6,9,13,17). Specific changes in plasma lipids may bypass the hyporesponsiveness of the HPA axis, stimulating steroidogenesis and increasing plasma concentrations of both mineralocorticoids and glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of the newborn to adapt to low O 2 depends on a multitude of physiological changes. These changes include, but are not limited to, shifts in metabolic, hemodynamic, digestive, and cardiorespiratory function (2,6,10,13,14,17,21,26,35). It has also become evident that there exists a unique developmental aspect to the maturation of the adrenocortical response to stress in the neonatal rat (1,33,37,38).…”

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confidence: 99%

Metabolomic analysis of adrenal lipids during hypoxia in the neonatal rat: implications in steroidogenesis

Bruder

Lee²,

Raff³

2004

American Journal of Physiology-Endocrinology and Metabolism

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analysis of adrenal lipids during hypoxia in the neonatal rat: implications in steroidogenesis. Am J Physiol Endocrinol Metab 286: E697-E703, 2004. First published January 6, 2004 10.1152/ajpendo. 00502.2003.-The nursing rat pup exposed to hypoxia from birth exhibits ACTH-independent increases in corticosterone and renin/ ANG II-independent increases in aldosterone. These increases are accompanied by significant elevation of plasma lipid concentrations in the hypoxic neonates. The purpose of the present study was to compare changes in the concentrations of specific fatty acid metabolites and lipid classes in serum and adrenal tissue from normoxic and hypoxic rat pups. We hypothesized that lipid alterations resulting from hypoxia may partly explain increases in steroidogenesis. Rats were exposed to normoxia or hypoxia from birth, and pooled serum and adrenal tissue from 7-day-old pups were subjected to metabolomic analyses. Hypoxia resulted in specific and significant changes in a number of fatty acid metabolites in both serum and the adrenal. Hypoxia increased the concentrations of oleic (18:1 n-9), eicosapentaenoic (EPA; 20:5 n-3), and arachidonic (20:4 n-6) acids in the triacylglyceride fraction of serum and decreased oleic and EPA concentrations in the cholesterol ester fraction. In the adrenal, hypoxia caused an increase in several n-6 fatty acids in the triacylglyceride fraction, including linoleic (18:2 n-6) and arachidonic acid. There was also an increase in the concentration of ␣-linolenic acid (18:3 n-3) in the triacylglyceride fraction of the hypoxic adrenal, along with an increase in linoleic acid concentration in the diacylglyceride fraction. We propose that specific changes in lipid metabolism in the adrenal, as a result of hypoxia, may partly explain the increased steroidogenesis previously observed. The mechanism responsible may involve alterations in cellular signaling and/or mitochondrial function. These cellular changes may be a mechanism by which the neonate can increase circulating adrenal steroids necessary for survival, therefore bypassing a relative insensitivity to normal stimuli.

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“…This is likely to maintain glucose delivery to the brain and heart under hypoxic conditions. Another phenomenon of particular interest is the effect of corticosterone on the development of the hepatic and exocrine pancreatic function, which we have shown is necessary to maintain neonatal hypoxic hyperlipidemia (15,16). Therefore, in addition to the clear effects of corticosterone on maintaining cardiovascular reactivity during hypoxia, the effects on intermediate metabolism in the neonatal pup are vital components in the adaptation to hypoxia.…”

Section: Perspectivesmentioning

confidence: 94%

Adrenocortical responses to ACTH in neonatal rats: effect of hypoxia from birth on corticosterone, StAR, and PBR

Raff

Hong

Oaks

et al. 2003

American Journal of Physiology-Regulatory, Integrative and Comp

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The adrenocortical response to hypoxia may be a critical component of the adaptation to this common neonatal stress. Little is known about adrenal function in vivo in hypoxic neonates. The purpose of this study was to evaluate adrenocortical responses to ACTH in suckling rat pups exposed to hypoxia from birth to 5-7 days of age compared with normoxic controls. We also evaluated potential cellular controllers of steroidogenic function in situ. In 7-day-old pups at 0800, hypoxia from birth resulted in increased basal (12.2 Ϯ 1.4 ng/ml; n ϭ 12) and ACTHstimulated (94.0 Ϯ 9.4 ng/ml; n ϭ 14) corticosterone levels compared with normoxic controls (basal ϭ 8.3 Ϯ 0.5 ng/ml; n ϭ 11; stimulated ϭ 51.3 Ϯ 3.8 ng/ml; n ϭ 8). This augmentation occurred despite no significant difference in plasma ACTH levels in normoxic vs. hypoxic pups before (85 Ϯ 4 vs. 78 Ϯ 8 pg/ml) or after (481 Ϯ 73 vs. 498 Ϯ 52 pg/ml) porcine ACTH injection (20 g/kg). This effect was similar in the afternoon at 6 days of age and even greater at 5 days of age at 0800. The aldosterone response to ACTH was not augmented by exposure to hypoxia from birth. Adrenocortical hypoxia-inducible factor (HIF)-1␣ mRNA was undetectable by RT-PCR. Steroidogenic acute regulatory (StAR) protein in adrenal subcapsules (zona fasciculata/reticularis) was augmented by exposure to hypoxia; this effect was greatest at 5 days of age. Peripheral-type benzodiazepine receptor (PBR) protein was also increased at 6 and 7 days of age in pups exposed to hypoxia from birth. We conclude that hypoxia from birth results in an augmentation of the corticosterone but not aldosterone response to ACTH. This effect appears to be mediated at least in part by an increase in controllers of mitochondrial cholesterol transport (StAR and PBR) and to occur independently of measurable changes in endogenous plasma ACTH. The augmentation of the corticosterone response to acute increases in ACTH in hypoxic pups is likely to be an important component of the overall physiological adaptation to hypoxia in the neonate. adrenocorticotropin; aldosterone; newborn; steroidogenic acute regulatory protein; peripheral-type benzodiazepine receptor; hypoxia-inducible factor HYPOXIA is one of the most common causes of neonatal morbidity and mortality (10, 17). Considerable attention has been paid to the short-and long-term neurological, cardiopulmonary, and renal consequences of neonatal hypoxia (3,8,14,34,36). In comparison, the adrenal adaptation in vivo to prolonged neonatal hypoxia has not been extensively studied. One pertinent study in human infants with hypoxemia due to bronchiolitis demonstrated an augmented cortisol, but not aldosterone, response to ACTH (12). This suggests a zone-specific adrenal adaptation to hypoxia.We have extensively examined dispersed adrenal cells in vitro removed from suckling rats exposed to hypoxia from birth (28). We have found that, as opposed to adult rats (29), steroidogenesis in vitro is augmented in adrenal cells from hypoxic neonatal rats despite no changes in steroidogenic enzy...

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Effect of neonatal hypoxia on the development of hepatic lipase in the rat

Cited by 21 publications

References 29 publications

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Metabolomic analysis of adrenal lipids during hypoxia in the neonatal rat: implications in steroidogenesis

Adrenocortical responses to ACTH in neonatal rats: effect of hypoxia from birth on corticosterone, StAR, and PBR

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