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K R Feingold

Publications and source records attributed to K R Feingold.

At least 163 records · Page 9Linked to original sources
PubMed1994

Endotoxin and cytokines increase hepatic messenger RNA levels and serum concentrations of apolipoprotein J (clusterin) in Syrian hamsters.

Infection and inflammation induce alterations in hepatic synthesis and plasma concentrations of the acute phase proteins. Our results show that apolipoprotein (apo) J is a positive acute phase protein. Endotoxin (LPS), tumor necrosis factor (TNF), and interleukin (IL)-1 increased hepatic mRNA and serum protein levels of apo J in Syrian hamsters. Hepatic apo J mRNA levels increased 10- to 15-fold with doses of LPS from 0.1 to 100 micrograms/100 g body weight within 4 h and were elevated for > or = 24 h. Serum apo J concentrations were significantly increased by 16 h and further elevated to 3.3 times that of control, 24 h after LPS administration. Serum apo J was associated with high density lipoprotein and increased fivefold in this fraction, after LPS administration. Hepatic apo J mRNA levels increased 3.5- and 4.6-fold, with TNF and IL-1, respectively, and 8.2-fold with a combination of TNF and IL-1. Serum apo J concentrations were increased 2.3-fold by TNF, 79% by IL-1, and 2.9-fold with a combination of TNF and IL-1. These results demonstrate that apo J is a positive acute phase protein.

Amino Acid Sequence↗
PubMed1994

Cytokine regulation of parathyroid hormone-related protein messenger ribonucleic acid levels in mouse spleen: paradoxical effects of interferon-gamma and interleukin-4.

Under normal physiological conditions, PTH-related protein (PTHrP) is produced in a wide variety of tissues and is thought to act locally in an autocrine or paracrine fashion more analogous to cytokines than to classic hormones such as PTH. In addition, we have recently shown that, like cytokines, PTHrP is induced in the spleen during the response to sublethal doses of endotoxin [lipopolysaccharide (LPS)] an effect that is mediated by tumor necrosis factor (TNF). As complex cytokine cascades are induced in response to infectious or inflammatory stimuli, the effects of other prototypical inflammatory [interferon-gamma (IFN gamma)] or antiinflammatory [interleukin-4 (IL-4)] cytokines on PTHrP gene expression were studied. Paradoxically, IFN gamma (50 micrograms), a cytokine that usually synergizes with TNF, inhibited LPS induction of splenic PTHrP messenger RNA (mRNA) levels in LPS-sensitive C3H/OuJ (OuJ) and LPS-resistant C3H/HeJ (HeJ) mice. The stimulation of splenic PTHrP mRNA levels caused by the administration of TNF alpha or interleukin-1 beta was similarly inhibited by IFN gamma, a type II interferon. In contrast, IFN alpha (50 micrograms), a type I interferon, stimulated splenic levels of PTHrP mRNA. IL-4, a prototypical antiinflammatory cytokine, also had a paradoxical effect on LPS induction of splenic PTHrP mRNA levels. Instead of inhibiting LPS induction of splenic PTHrP mRNA levels in OuJ or HeJ mice, IL-4 (200 ng) actually stimulated PTHrP mRNA levels. These complex cytokine interactions suggest that the expression of PTHrP in response to infectious or inflammatory stimuli depends on the counterbalancing effects of the specific cytokine networks induced by each stimulus.

Animals↗
PubMed1994

Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes.

Cytokines induce a number of changes in lipid metabolism that can produce hyperlipidemia. Leukemia inhibitory factor (LIF), a recently discovered cytokine, has been suggested to play a role in the cancer cachexia syndrome through its ability to decrease lipoprotein lipase (LPL) activity. This study explores the mechanism by which LIP decreases LPL activity in cultured adipocytes and determines its effects on fatty acid synthesis and lipolysis to see if it shares the same catabolic effects on fat cells as seen with other cytokines, such as tumor necrosis factor (TNF). LIF decreased LPL activity in cultured adipocytes by 44% compared with an 85% decrease produced by TNF. Although the percent decrease in LPL activity is not as great in LIF-incubated adipocytes as in TNF-incubated adipocytes, the half-maximal doses for both cytokines are similar. LPL messenger RNA levels paralleled LPL activity in the LIF-treated adipocytes, suggesting that the effect of LIF on LPL activity is predominantly mediated through transcriptional regulation. In contrast to TNF, LIF tended to increase the de novo synthesis of fatty acids. Acetyl coenzyme-A carboxylase messenger RNA levels paralleled the changes seen in fatty acid synthesis for both cytokines. LIF caused a small increase in lipolysis, whereas TNF increased lipolysis by greater than 2-fold. These results demonstrate that the catabolic effects of LIF are weaker than those of TNF and are predominantly directed toward decreasing LPL activity, which may contribute to the hyperlipidemia associated with infection, inflammation, and cancer.

3T3 Cells↗
PubMed1994

Alpha-adrenergic receptors mediate the hypertriglyceridemia induced by endotoxin, but not tumor necrosis factor, in rats.

We assessed the role of catecholamines in mediating the hypertriglyceridemia induced by lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF alpha) in rats by employing specific adrenoreceptor antagonists. Pretreatment with phentolamine, an alpha-antagonist, but not propranolol, a beta-antagonist, suppressed the hypertriglyceridemia induced by either low dose LPS (100 ng/100 g BW) or high dose LPS (50 micrograms/100 g BW). Prazosin, an alpha 1-selective antagonist, significantly suppressed the low dose LPS-induced hypertriglyceridemia by inhibiting hepatic triglyceride secretion, but did not affect the increase in lipolysis. In contrast, yohimbine, an alpha 2-selective antagonist, partially suppressed the high dose LPS-induced hypertriglyceridemia by inhibiting the decrease in postheparin lipoprotein lipase activity. Treatment with phentolamine and propranolol did not affect the hypertriglyceridemia induced by TNF alpha. In summary, these findings suggest that catecholamines via alpha-adrenergic, but not beta-adrenergic, receptors are mediators of the hypertriglyceridemia induced by either low or high dose LPS in rats. alpha 1-Adrenergic receptors are involved in mediating the increased hepatic triglyceride secretion induced by low dose LPS, whereas alpha 2-adrenergic receptors are involved in mediating the decrease in lipoprotein lipase activity induced by high dose LPS. The hypertriglyceridemia induced by either low or high dose LPS may be regulated by a mechanism unrelated to TNF alpha in rats.

Adrenergic alpha-Antagonists↗
PubMed1994

Effects of TNF, IL-1, and the combination of both cytokines on cholesterol metabolism in Syrian hamsters.

Infection and inflammation are associated with alterations in lipid metabolism that may be mediated by cytokines such as TNF and IL-1. This study determined the effects of TNF and IL-1 on certain aspects of cholesterol metabolism. TNF or IL-1 administration to Syrian hamsters increased serum cholesterol levels by 17 and 21%, respectively, and decreased HDL cholesterol levels by 20 and 15%, respectively. TNF + IL-1 increased serum cholesterol levels by 58% and decreased HDL cholesterol levels by 58%. TNF or IL-1 increased hepatic HMG CoA reductase mRNA levels by 3.5- and 3-fold, respectively. TNF + IL-1 increased HMG CoA reductase mRNA levels by 7-fold. IL-1 increased hepatic LDL receptor mRNA levels by 2-fold while TNF and a combination of TNF + IL-1 had minimal effects. TNF or IL-1 did not affect hepatic apo E or apo A-I mRNA levels while a combination of TNF + IL-1 decreased both mRNA levels by 50%. Our results demonstrate that TNF and IL-1 similarly affect the parameters of cholesterol metabolism studied. Furthermore, the combination of TNF + IL-1 was, in most cases, more effective than either cytokine alone, and reproduced many of the effects of LPS.

Animals↗
PubMed1994

Permeability barrier requirements regulate epidermal beta-glucocerebrosidase.

The intercellular spaces of the outermost layers of the epidermis (stratum corneum, SC) of terrestrial mammals contain a mixture of lipids, enriched in ceramides that are critical for the epidermal permeability barrier. Whereas glucosylceramides (GlcCer) are synthesized in abundance in the epidermis, they disappear coincident with an increase of ceramides (Cer) in the SC. Hence, hydrolysis of GlcCer to Cer by beta-glucocerebrosidase (GlcCer'ase), may be required for permeability barrier homeostasis. We determined first whether modulations in epidermal GlcCer'ase activity and mRNA levels occur in response to barrier disruption; and second, how GlcCer'ase inhibitors influence barrier function and SC membrane ultrastructure. Barrier disruption significantly increased epidermal GlcCer'ase mRNA levels, with a 2.8-fold increase over untreated control levels at 8 h (P < 0.01). GlcCer'ase activity was increased in whole epidermis (34%; P < 0.02) 24 h after barrier disruption. Localization of GlcCer'ase activity showed an increase (33%; P < 0.05) in the outer epidermis (SC and stratum granulosum), without a change in lower epidermal activity (stratum spinosum and stratum basale). Furthermore, a single topical application of the GlcCer'ase inhibitor, bromoconduritol-B-epoxide (BrCBE), inhibited enzyme activity (98%) and significantly delayed permeability barrier recovery after acetone treatment. In addition, BrCBE treatment disrupted SC intercellular lamellar bilayers, without evidence of cellular toxicity. These results indicate that epidermal processing of GlcCer to Cer by GlcCer'ase is required for barrier homeostasis, and that this important enzymatic step is regulated by barrier requirements.

Acetone↗
PubMed1993

Lipopolysaccharide stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation.

A role for immune and inflammatory processes in the induction of atherosclerotic lesions is emerging. These studies were undertaken to determine whether activation by lipopolysaccharide (LPS) enhances the ability of macrophages to become foam cells. Since LPS activation inhibits scavenger receptor activity, we studied the ability of LPS-activated RAW 264.7 macrophages to accumulate lipid from a variety of lipid particles that are not ligands for the scavenger receptor. Macrophages activated by LPS, in the absence of lipid particles, accumulated triglyceride, but not cholesterol ester (CE). The addition of Soyacal, a triglyceride-rich particle, further enhanced this LPS-stimulated triglyceride accumulation. LPS activation similarly enhanced CE accumulation almost 3-fold from two CE-rich lipoproteins, beta VLDL and LDL, as compared with controls. The unstimulated control cells only accumulated significant CE from beta VLDL and not LDL. LPS-enhanced lipid accumulation was dependent on LPS dose and began after 8-12 h of incubation. LPS increased the degradation of 125I-labelled LDL and the cell-associated 125I-labelled LDL at 37 degrees C by 1.8-fold. Degradation remained saturable, consistent with a receptor-mediated process. Antioxidants did not inhibit LPS-induced CE accumulation from LDL. Thus, activation of RAW 264.7 macrophages enhanced their ability to accumulate lipid from a variety of lipid particles and to become foam cells. These data suggest a potential role for infections, and LPS in particular, in atherogenesis.

Animals↗
PubMed1993

Relationship of apolipoprotein E phenotypes to hypocholesterolemia.

PURPOSE: Persons with total cholesterol (TC) levels less than 130 mg/dL (less than 3.26 mmol/L) make up less than 1% of a healthy population. Causes of hypocholesterolemia include a diet very low in cholesterol and saturated fat, disease, genetic factors (including low apolipoprotein B-100 [apo B-100] and the apo E allele), and drug therapy. The purpose of this study was to determine the causes of hypocholesterolemia in a healthy Kaiser Foundation Health Plan (KFHP) population. PATIENTS AND METHODS: We conducted a dietary and health survey of 201 healthy hypocholesterolemic adults (range: 2.04 to 3.88 mmol/L [79 to 150 mg/dL]) and 200 matched control subjects with TC levels in the middle quintile of the population (range: 5.0 to 5.61 mmol/L [194 to 217 mg/dL]) who had routine health screening from 1983 through 1985. We did apo E phenotyping studies and lipid and apo A-1 and B-100 measurements in a subgroup of 45 hypocholesterolemic subjects (mean TC level: 3.26 mmol/L [126 mg/dL]) and in a comparison group of 49 unmatched volunteers (mean TC level: 5.04 +/- 0.75 mmol/L [195 +/- 29 mg/dL]). RESULTS: We found no differences in dietary intake or clinically significant medical illness between hypocholesterolemic and control subjects. In the hypocholesterolemic subgroup, we found an increased frequency of the apo E2 allele (epsilon 2) and a decreased frequency of the apo E4 allele (epsilon 4); the frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles were 33.3%, 63.3%, and 3.3%, respectively. The corresponding apo E allele frequencies in the comparison subgroup were 8.2%, 73.5%, and 18.4%, similar to those previously reported for the general population and significantly different from those found in the hypocholesterolemic subgroup (p < 0.0001). One hypocholesterolemic subject (a 46th patient) had a mutation in the apo B gene that resulted in the synthesis of a truncated species of apo B (apo B-46). CONCLUSION: Our study indicates that hypocholesterolemia in our KFHP urban population is usually not caused by diet or disease. Biochemical factors, including the increased frequency of the apo E-2 phenotype and the decreased frequency of the apo E-4 phenotype, are more important.

Adult↗
PubMed1993

Indices of thyroid function and weight loss in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.

Abnormalities of thyroid hormone levels have been reported in the acquired immunodeficiency syndrome (AIDS), but there has been debate as to whether they are appropriate for the clinical status of the patients. Inappropriate maintenance of circulating 3,3',5-triiodothyronine (T3) levels could contribute to weight loss. Although many patients with AIDS have a history of wasting, recent data indicate that prolonged periods of stable weight occur in AIDS and that short-term weight loss is present in a subset of patients with anorexia, many of whom have active secondary infection (AIDS-SI). Therefore we analyzed thyroid hormone levels in a cohort of subjects that have been characterized in terms of recent weight loss and caloric intake. Asymptomatic patients with human immunodeficiency virus infection (HIV+) had short-term stable weights, normal caloric intake, and normal serum T3 levels. In AIDS, average short-term weight was stable, caloric intake was normal, and T3 levels were decreased by 19%. In AIDS-SI, both short-term weight loss and anorexia were significant, and this group showed a 45% decrease in T3 levels. The free T3 (FT3) index was decreased by 30% in AIDS and by 50% in AIDS-SI. Free thyroxine (FT4) levels were decreased while thyroxine-binding globulin (TBG) capacity was increased in HIV+ and AIDS; TBG sialylation was unchanged. Thyrotropin (TSH) levels were slightly increased in AIDS, although levels remained within the normal range. 3,3',5'-triiodothyronine (rT3) levels were decreased in HIV+, AIDS, and AIDS-SI. Thus asymptomatic patients with HIV infection whose weight is stable maintain normal T3 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1993

Inhibition of cholesterol and sphingolipid synthesis causes paradoxical effects on permeability barrier homeostasis.

Cholesterol, fatty acid, and sphingolipid synthesis are required for barrier homeostasis, as demonstrated by studies where synthesis of these species is stimulated in parallel with barrier repair. Moreover, blockade of synthesis of these lipids with inhibitors of two of the rate-limiting enzymes, HMGCoA reductase (lovastatin, fluvastatin) and serine palmitoyl transferase (beta-chloroalanine), alters the kinetics of barrier repair. Whereas these studies demonstrated a requirement for these lipids individually, we asked here whether these lipids are required in either an additive or cooperative fashion. We applied each class of inhibitor alone or the two classes of inhibitors together to acetone-treated skin, or each class separately to essential fatty acid deficient murine skin. When fluvastatin or beta-chloroalanine was applied individually to acetone-treated skin, each caused a delay in the early or late stages of barrier recovery, respectively (assessed as transepidermal water loss). However, when applied together they caused no further worsening at the early time point and a paradoxical improvement at the later time points. This improvement correlated with an accelerated return of sphingolipids, which was perhaps due to a global stimulation of lipid synthesis induced by HMGCoA reductase inhibitors. In essential fatty acid deficient animals, inhibition of HMGCoA reductase caused drastic worsening of both clinical appearance and barrier function, but beta-chloroalanine caused a paradoxical improvement, which correlated with a significant reduction in epidermal sphingolipids. These results are consistent with a requirement for both cholesterol and sphingolipids for barrier homeostasis, and also with the suggestion that both of these lipids must be present (with free fatty acids) for optimal barrier function.

Acetone↗
PubMed1993

Barrier function regulates epidermal lipid and DNA synthesis.

The stratum corneum, the permeability barrier between the internal milieu and the environment, is composed of fibrous protein-enriched corneocytes and a lipid-enriched intercellular matrix. The lipids are a mixture of sphingolipids, cholesterol and free fatty acids, which form intercellular membrane bilayers. Lipid synthesis occurs in the keratinocytes in all nucleated layers of the epidermis, and the newly synthesized lipids are delivered by lamellar bodies to the interstices of the stratum corneum during epidermal differentiation. Disruption of barrier function by topical acetone treatment results in an increase in the synthesis of free fatty acids, sphingolipids and cholesterol in the living layers of the epidermis, leading to barrier repair. Cholesterol and sphingolipid synthesis are regulated by the rate-limiting enzymes HMG CoA reductase and serine palmitoyl transferase (SPT), respectively. Acute barrier disruption leads to an increase in both enzymes, but with a different time curve: increase in HMG CoA reductase activity begins at 1.5 h, whereas the increase in SPT activity occurs 6 h after barrier impairment. Topical application of HMG CoA reductase or SPT inhibitors after acetone treatment delays barrier repair, providing further evidence for a role of cholesterol and sphingolipids in epidermal barrier function. Repeated application of lovastatin to untreated skin results in disturbed barrier function accompanied by increased DNA synthesis and epidermal hyperplasia. Therefore, we have examined the specific relationship between barrier function and epidermal DNA synthesis. After acute and chronic disturbances not only lipid, but also DNA synthesis, is stimulated. Thus, stimulation of DNA synthesis leading to epidermal hyperplasia may be a second mechanism by which the epidermis repairs defects in barrier function. The link between barrier function and both lipid and DNA synthesis is supported further by occlusion studies. Artificial barrier repair by latex occlusion prevents an increase in both lipid and DNA synthesis. In addition, increased epidermal lipid and DNA synthesis in essential fatty-acid deficiency can be reversed by topical applications of the n-6 unsaturated fatty acids, linoleic or columbinic acid. These studies may be of relevance in understanding the pathogenesis of hyperproliferative skin diseases, such as ichthyosis, psoriasis, atopic dermatitis, and irritant contact dermatitis.

Animals↗
PubMed1993

Chylomicrons enhance endotoxin excretion in bile.

Chylomicrons prevent endotoxin toxicity and increase endotoxin uptake by hepatocytes. As a consequence, less endotoxin is available to activate macrophages, thereby reducing tumor necrosis factor secretion. To determine whether the chylomicron-mediated increase in hepatocellular uptake of endotoxin results in increased endotoxin excretion into bile, we examined bile after endotoxin administration. A sublethal dose (7 micrograms/kg) of 125I-endotoxin was incubated with either rat mesenteric lymph containing nascent chylomicrons (500 mg of chylomicron triglyceride per kg of body weight) or an equal volume of normal saline (controls) for 3 h and then infused into male Sprague-Dawley rats. Bile samples were collected via a common bile duct catheter for 24 h. Infusion of endotoxin incubated with chylomicrons increased biliary excretion of endotoxin by 67% at 3 h (P < or = 0.006) and by 20% at 24 h (P < or = 0.01) compared with infusion of endotoxin incubated in saline. Endotoxin activity, as measured by the Limulus assay, was not detected in the bile of test animals. However, endotoxin activity was detected after hot phenol-water extraction of bile, demonstrating that endotoxin is inactive in the presence of bile but retains bioactivity after hepatic processing. Since the majority of an intravenous endotoxin load has been shown to be cleared by the liver, acceleration of hepatocyte clearance and biliary excretion of endotoxin may represent a component of the mechanism by which chylomicrons protect against endotoxin-induced lethality.

Animals↗
PubMed1993

Extrahepatic lipogenesis contributes to hyperlipidemia in the analbuminemic rat.

Hepatic lipid and apolipoprotein synthesis is increased in the nephrotic syndrome. Catabolism of triglyceride-rich lipoproteins is impaired in nephrotic syndrome but not in rats with hereditary analbuminemia (NA), suggesting that lipid synthesis should be increased by analbuminemia in the absence of proteinuria. In this study the rate of cholesterol and fatty acid synthesis in liver and extrahepatic tissue was measured in female NA and control Sprague-Dawley (SD) rats to determine whether lipid synthesis was indeed increased in isolated analbuminemia and to identify the site(s) of increased lipogenesis. We also measured the concentrations of apolipoproteins (apo) AI, B, and E in plasma, as well as the levels of the respective mRNAs in liver. Plasma cholesterol, triglycerides, and apo AI, B, and E were all increased severalfold in the NA rat (P < 0.001). Although liver apolipoprotein mRNA content was significantly increased (P < 0.001) for apo AI (643%), B (273%), and E (299%), 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in liver microsomes and hepatic cholesterol synthesis were not significantly increased in the NA rats. Hepatic fatty acid synthesis and intestinal cholesterol synthesis were not increased in the NA rats. Surprisingly, intestinal fatty acid synthesis was elevated by 60% (P < 0.01). The NA rats demonstrated approximately fourfold increases in the incorporation of 3H2O into circulating cholesterol and fatty acids (P < 0.001). A 56% increase in the synthesis of total nonsaponifiable lipid was found in the extravisceral carcass (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.

Animals↗
PubMed1993

Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

The interstices of the mammalian stratum corneum contain lipids in a system of continuous membrane bilayers critical for the epidermal permeability barrier. During the transition from inner to outer stratum corneum, the content of polar lipids including glucosylceramides, decreases while ceramide content increases. We investigated whether inhibition of glucosylceramide hydrolysis would alter epidermal permeability barrier function. Daily topical applications of bromoconduritol B epoxide (BrCBE) to intact murine skin selectively inhibited beta-glucocerebrosidase, increased glucosylceramide content of stratum corneum with ceramide content remaining largely unchanged, and caused a progressive, reversible decrease in barrier function. Histochemistry of inhibitor-treated epidermis revealed persistence of periodic acid-Schiff-positive staining in stratum corneum cell membranes, consistent with retention of hexose moieties. Electron microscopy of inhibitor-treated samples revealed no evidence of toxicity or changes in the epidermal lipid delivery system. However, immature membrane structures persisted in the intercellular spaces throughout the stratum corneum, with reappearance of mature membrane structures progressing outward from the lower stratum corneum upon termination of BrCBE. Finally, the induced barrier abnormality was not reversed by coapplications of ceramide. These data demonstrate that glucosylceramide hydrolysis is important in the formation of the epidermal permeability barrier, and suggest that accumulation of glucosylceramides in stratum corneum intercellular membrane domains leads to abnormal barrier function.

Administration, Topical↗
PubMed1993

Glucocorticoids accelerate fetal maturation of the epidermal permeability barrier in the rat.

The cutaneous permeability barrier to systemic water loss is mediated by hydrophobic lipids forming membrane bilayers within the intercellular domains of the stratum corneum (SC). The barrier emerges during day 20 of gestation in the fetal rat and is correlated with increasing SC thickness and increasing SC lipid content, the appearance of well-formed lamellar bodies in the epidermis, and the presence of lamellar unit structures throughout the SC. Because glucocorticoids accelerate lung lamellar body and surfactant maturation in man and experimental animals, these studies were undertaken to determine whether maternal glucocorticoid treatment accelerates maturation of the epidermal lamellar body secretory system. Maternal rats were injected with betamethasone or saline (control) on days 16-18, and pups were delivered prematurely on day 19. Whereas control pups exhibited immature barriers to transepidermal water loss (8.16 +/- 0.52 mg/cm2 per h), glucocorticoid-treated pups exhibited competent barriers (0.74 +/- 0.14 mg/cm2 per h; P < 0.001). Glucocorticoid treatment also: (a) accelerated maturation of lamellar body and SC membrane ultrastructure; (b) increased SC total lipid content twofold; and (c) increased cholesterol and polar ceramide content three- to sixfold. Thus, glucocorticoids accelerate the functional, morphological, and lipid biochemical maturation of the permeability barrier in the fetal rat.

Animals↗
PubMed1993

The effect of oxidized lipids in the diet on serum lipoprotein peroxides in control and diabetic rats.

The levels of oxidized serum lipoproteins are increased in humans and animals with diabetes. We have examined the contribution of dietary oxidized lipids on the levels of oxidized lipoproteins. In both control and streptozocin induced diabetic rats, the oxidized lipid content of mesenteric lymph chylomicrons (CM) increased when increasing quantities of oxidized lipids were administered intragastrically. However, at all levels of administered oxidized lipids, the quantity of oxidized lipids in CM was greater in the diabetic animals. These results indicate that oxidized lipids are absorbed and packaged into CM and suggest that there is increased absorption of oxidized lipids in diabetic animals. In nondiabetic rats fed a fat-free diet, the levels of oxidized lipids in their serum lipoproteins were very low. When oxidized lipids were added to the diet, the quantity of peroxides in serum lipoproteins increased about fivefold. In diabetic animals fed a fat-free diet, there were also very low levels of oxidized lipids in their serum lipoproteins, and there was no difference between control and diabetic rats. However, when diabetic animals were fed a diet containing oxidized lipids, the quantity of oxidized lipids in their serum lipoproteins increased 16-fold and were significantly greater than in controls. Thus, in both control and diabetic rats the quantity of oxidized lipids in the diet largely determines the levels of oxidized lipids in circulating lipoproteins. However, in diabetic animals the effect of diet is more pronounced. Together with the CM studies, these results demonstrate that dietary oxidized lipids make a major contribution to the levels of oxidized lipids in circulating lipoproteins and indicate that increased absorption of oxidized lipids in diabetic animals may play a role in the elevation of oxidized lipoproteins observed in this disorder.

Animals↗