Metabolic disturbances and wasting in the acquired immunodeficiency syndrome.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
K R Feingold
Publications and source records attributed to K R Feingold.
Cytokines stimulate lipolysis and decrease lipoprotein lipase activity in cultured fat cells by a prostaglandin independent mechanism.
We previously showed that indomethacin blocked the effect of tumor necrosis factor (TNF) and other cytokines on lipolysis. We now show that TNF stimulates prostaglandin (PG) production, enhances lipolysis and decreases lipoprotein lipase (LPL) activity in 3T3-F442A adipocytes and indomethacin blocks these activities, suggesting that the actions of TNF are mediated by PG's. However, exogenous PGE2 at the levels induced by TNF is not sufficient to affect lipolysis or LPL activity and low doses of indomethacin and flurbiprofen block PG production without affecting TNF's action. Interleukin-1 and interferon-alpha and gamma induce lipolysis and decrease LPL activity but do not stimulate much PG production. These results demonstrate that cytokines enhance lipolysis and decrease LPL activity in 3T3 adipocytes by a PG independent mechanism.
3T3 Cells↗
Localization of calcium in murine epidermis following disruption and repair of the permeability barrier.
Perturbation of the cutaneous permeability barrier results in rapid secretion of epidermal lamellar bodies, and synthesis and secretion of new lamellar bodies leading to barrier repair. Since external Ca2+ significantly impedes the repair response, we applied ion capture cytochemistry to localize Ca2+ in murine epidermis following barrier disruption. In controls, the numbers of Ca2+ precipitates in the basal layer were small, increasing suprabasally and reaching the highest density in the stratum granulosum. Barrier disruption with acetone produced an immediate, marked decrease in Ca2+ in the stratum granulosum, accompanied by secretion of lamellar bodies. Loss of this pattern of Ca2+ distribution was associated with the appearance of large Ca2+ aggregates within the intercellular spaces of the stratum corneum. The Ca(2+)-containing precipitates progressively reappeared in parallel with barrier recovery over 24 h. Disruption of the barrier with tape stripping also resulted in loss of Ca2+ from the nucleated layers of the epidermis, but small foci persisted where the stratum corneum was not removed; in these sites the Ca2+ distribution did not change and accelerated secretion of lamellar bodies was not observed. Following acetone-induced barrier disruption and immersion in isoosmolar sucrose, the epidermal Ca2+ gradient did not return, and both lamellar body secretion and barrier recovery occurred. However, with immersion in isoosmolar sucrose plus Ca2+, the epidermal Ca2+ reservoir was replenished, and both secretion of lamellar bodies and barrier recovery were impeded. These results demonstrate that barrier disruption results in loss of the epidermal Ca2+ reservoir, which may be the signal that initiates lamellar body secretion leading to barrier repair.
Acetone↗
Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
To assess the causes of short-term weight loss in patients with acquired immunodeficiency syndrome (AIDS), we measured resting energy expenditure (REE), caloric intake, and the 28-d weight trend in control subjects, human immunodeficiency virus (HIV)+ subjects, AIDS patients, and AIDS patients during secondary infection (AIDS-SI). REE was increased in HIV+ (11%), AIDS (25%), and AIDS-SI (29%). Caloric intake was similar in control subjects, HIV+, and AIDS but reduced 36% in AIDS-SI, who consumed 17% fewer calories than their REE. Average short-term weight was stable for HIV+ and AIDS but decreased 5% in AIDS-SI. Weight trend correlated with caloric intake but not with REE. Thus HIV+ and AIDS are able to partially compensate for increased REE because they do not show short-term weight loss. Decreased caloric intake is critical for short-term weight loss and is seen during secondary infection. Inability of decreased caloric intake to decrease REE during infection accelerates short-term weight loss. Rapid weight loss with anorexia may be a harbinger of secondary infection in AIDS.
Acquired Immunodeficiency Syndrome↗
The role of the cytokines, interferon alpha and tumor necrosis factor in the hypertriglyceridemia and wasting of AIDs.
The hypertriglyceridemia of infection is mediated by many of the cytokines that regulate the immune response, including the tumor necrosis factors, the interleukins and the interferons. In the acquired immunodeficiency syndrome (AIDS), hypertriglyceridemia is most likely due to increased circulating levels of interferon alpha. Both in AIDS and in animal models there is no direct association between the presence of hypertriglyceridemia and the syndrome of wasting. Rather, circulating lipoproteins may neutralize infectious organisms and therefore contribute to host defense.
Acquired Immunodeficiency Syndrome↗
Lamellar body secretory response to barrier disruption.
Abundant evidence points to an important role for epidermal lamellar body secretion in permeability-barrier maintenance. However, the response of the lamellar body secretory system to barrier disruption has not been examined. Hence, we examined the lamellar body secretory response at various points after acetone-induced barrier abrogation in hairless mice in air-exposed animals and those occluded with impermeable versus vapor-permeable membranes. Tape-stripped animals served as a control for chemical toxicity. Barrier perturbation with either acetone or tape stripping was followed by rapid secretion of lamellar body contents from the uppermost granular cell layer, leaving the cytosol largely devoid of lamellar bodies. The newly secreted lamellar body contents comprised pleated sheets (not "discs," as previously thought), which unfurled in the intercellular spaces at the granular-cornified cell interface. At this time (15-30 min), the basic unit structure of the lamellar bilayers in the mid-to-upper stratum corneum appeared disorganized and interspersed with large lacunae, reflecting solvent extraction. Nascent lamellar bodies began to reappear in the granular cell cytosol by 30 min and by 360 min the cells displayed a full complement of normal-appearing lamellar bodies. Between 60 and 360 min, the density of lamellar body sheets at the granular-cornified cell interface increased, whereas the membrane bilayers of the outer stratum corneum remained disorganized. New lamellar bilayer units first appeared in the lower stratum corneum between 60 and 180 min, as a result of the transformation of secreted lamellar body sheets and over time these lamellae appeared at more apical locations. Occlusion with a water vapor-impermeable but not a vapor-permeable membrane resulted in a) decreased quantities of lamellar bodies and lamellar body-derived intercellular products; b) formation of lamellar bodies with abnormal internal contents; c) inhibition of lamellar body secretion; and d) inhibition of transformation of lamellar body-derived sheets into lamellar bilayer units. These results demonstrate the central role of the lamellar body-secretory system in barrier repair and homeostasis.
Acetone↗
Structural basis for the barrier abnormality following inhibition of HMG CoA reductase in murine epidermis.
Recent studies have shown that increased epidermal 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase activity is crucial for the barrier recovery response that follows solvent-induced barrier perturbation. Upregulation of this enzyme leads to increased cholesterologenesis, formation and secretion of cholesterol-enriched lamellar bodies, and barrier repair. Topical lovastatin-induced inhibition of HMG CoA reductase activity both delays the acute barrier-repair response, as well as leading to a chronic barrier abnormality when applied repeatedly to intact skin. Presently, we assessed the effects of repeated topical applications of two different specific inhibitors of HMG CoA reductase on barrier function, the lamellar body-secretory system, and stratum corneum intercellular domains, with functional and morphologic parameters. Once-daily applications of lovastatin or fluindostatin (XU62-320; Sandoz) for 4-8 d to intact hairless mouse epidermis produced a progressive abnormality in barrier function (transepidermal water loss greater than 2.0-5.0 in treated versus less than 0.25 mg/cm2/h for weakly active analogues or vehicle controls). The barrier defect was preceded by alterations in lamellar body internal structure and a partial failure of lamellar body secretion into the stratum corneum interstices, further confirmed by enzyme cytochemistry. Moreover, the deposition of abnormal lamellar body contents resulted in the formation of clefts in the intercellular spaces at the stratum granulosum-stratum corneum interface, resulting in increased permeability through these domains shown by lanthanum perfusion. Applications of irritants, even when producing a barrier abnormality, did not alter the lamellar body secretory system. Co-applications of cholesterol with the inhibitors reversed both the barrier abnormality and the abnormalities in the lamellar body secretory system that occur with the inhibitor alone. Finally, membrane bilayer structures in the mid-to-outer stratum corneum of inhibitor-treated specimens appeared normal, but the intercellular domains displayed enormously expanded lacunae. However, because similar dilatations also occurred in vehicle-treated samples, they can be attributed to the vehicle alone. These studies provide further evidence that the inhibitor-induced defect in barrier function a) is initiated by inhibition of HMG CoA reductase; b) can be attributed to defects in both lamellar body structure and deposition with resultant abnormalities in intercellular membrane domains in the lower stratum corneum; and c) is further enhanced by permissive effects of the vehicle on the permeability of the outer stratum corneum.
Alkanes↗
Epidermal HMG CoA reductase activity in essential fatty acid deficiency: barrier requirements rather than eicosanoid generation regulate cholesterol synthesis.
We showed previously that the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol biosynthesis, increases after both barrier disruption with organic solvents and in essential fatty acid deficiency (EFAD). Here, we treated EFAD hairless mice with linoleic acid, columbinic acid (C18: 3, n-6, trans; not metabolizable to known regulatory eicosanoids), prostaglandin E2 (PGE2), or latex occlusion, and determined transepidermal water loss (TEWL), epidermal protein content, and epidermal HMG CoA reductase activity. Increased TEWL rates in EFAD were accompanied by increased HMG CoA reductase activity (+130%, n = 6, p less than 0.01) and protein content (+69%; n = 6, p less than 0.025). Artificial restoration of the barrier by occlusion reduced the increase in enzyme activity and protein content toward normal, but barrier function, measured immediately after removal of the latex wrap, deteriorated further (TEWL: two-fold greater than EFAD unoccluded; p less than 0.01). Topical applications of either linoleate or columbinate (but not PGE2), normalized barrier function, HMG CoA reductase activity, and protein content. These results show that a) barrier function modulates HMG CoA reductase activity; b) reduction of cholesterol synthesis with occlusion results in a further deterioration in barrier function, suggesting that increased synthesis is a protective homeostatic response; and c) the barrier abnormality reflects a requirement for specific fatty acids for the barrier rather than resulting from epidermal hyperplasia or decreased prostaglandin generation.
Animals↗
Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
To determine the role of cytokines in mediating the decrease in ketones associated with infection, we studied the effect of endotoxin (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) on serum and hepatic ketone body levels (KB), serum free fatty acids (FFA), and hepatic malonyl-CoA levels. LPS decreased serum and hepatic KB in C57Bl/6 (LPS sensitive) mice, whereas it had little effect in C3H/HeJ (LPS resistant) mice, whose macrophages lack the ability to produce IL-1 and TNF in response to LPS, suggesting that IL-1 and TNF may mediate this effect. IL-1 and TNF decreased serum KB in both strains of mice. As seen with LPS, IL-1 decreased hepatic KB, whereas TNF had no such effect. LPS, IL-1, and TNF increased hepatic malonyl-CoA levels. TNF acutely raised serum FFA, whereas LPS and IL-1 did not. Postulating that the TNF-induced increase in FFA overrides the inhibitory effect of malonyl-CoA on fatty acid oxidation and ketogenesis, we used R-2-phenylisopropyladenosine to block TNF-induced lipolysis and demonstrated that in the absence of increased fatty acid flux, TNF inhibits KB formation. As seen with LPS, IL-1, but not TNF, decreased KB in the fasting state. These data suggest that IL-1 and TNF may mediate the antiketogenic effect of infection and that IL-1 has properties closest to that of LPS.
Animals↗
LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes.
Plasma low density lipoprotein (LDL) comprises multiple discrete subclasses differing in size, density, and chemical composition. A common, heritable phenotype characterized by the predominance of small, dense LDL particles (LDL subclass phenotype B) is associated with relatively increased concentrations of plasma triglycerides, reduced levels of high density lipoprotein, and increased risk of coronary artery disease in comparison with subjects with larger LDL (LDL subclass phenotype A). Population studies have indicated that approximately 20-30% of adult men have phenotype B, and another 15-20% have LDL of intermediate size. The lipid changes in phenotype B are similar to those that have been observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). In the present study, we have assessed LDL subclass phenotypes in normolipidemic men with NIDDM and in age-matched control subjects who had similar lipid levels. There was a greater than twofold increase in the percentage of individuals with the LDL B phenotype in the NIDDM subjects. The LDL B phenotype was associated with higher plasma triglyceride levels and a trend toward lower high density lipoprotein cholesterol levels compared with the LDL A phenotype in the NIDDM subjects, as has been previously observed in control groups. Indices of diabetic control, such as fasting and hemoglobin A1 levels, were similar regardless of LDL phenotype pattern, suggesting that glycemic control was not likely to account for the increase in the LDL B phenotype. In both control and NIDDM subjects, the clearance of triglyceride-rich lipoproteins was slowed in the subjects with the LDL phenotype B compared with those with the A phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Calcium and potassium are important regulators of barrier homeostasis in murine epidermis.
Topical solvent treatment removes lipids from the stratum corneum leading to a marked increase in transepidermal water loss (TEWL). This disturbance stimulates a variety of metabolic changes in the epidermis leading to rapid repair of the barrier defect. Using an immersion system we explored the nature of the signal leading to barrier repair in intact mice. Initial experiments using hypotonic to hypertonic solutions showed that water transit per se was not the crucial signal. However, addition of calcium at concentrations as low as 0.01 mM inhibited barrier repair. Moreover, both verapamil and nifedipine, which block calcium transport into cells, prevented the calcium-induced inhibition of TEWL recovery. Additionally, trifluoroperazine or N-6-aminohexyl-5-chloro-1-naphthalenesulfonamide, which inhibit calmodulin, prevented the calcium-induced inhibition of TEWL recovery. Although these results suggest an important role for calcium in barrier homeostasis, calcium alone was only modestly effective in inhibiting TEWL recovery. Potassium alone (10 mM) and phosphate alone (5 mM) also produced a modest inhibition of barrier repair. Together, however, calcium and potassium produced a synergistic inhibition of barrier repair (control 50% recovery vs. calcium + potassium 0-11% recovery in 2.5 h). Furthermore, in addition to inhibiting TEWL recovery, calcium and potassium also prevented the characteristic increase in 3-hydroxy-3-glutaryl CoA reductase activity that occurs after barrier disruption. Finally, the return of lipids to the stratum corneum was also blocked by calcium and potassium. These results demonstrate that the repair of the epidermal permeability barrier after solvent disruption can be prevented by calcium, potassium, and phosphate. The repair process may be signalled by a decrease in the concentrations of these ions in the upper epidermis resulting from increased water flux leading to passive loss of these ions.
Animals↗
Role for monokines in the metabolic effects of endotoxin. Interferon-gamma restores responsiveness of C3H/HeJ mice in vivo.
To examine the role of cytokines in mediating the lipogenic effects of endotoxin (LPS), we studied the effects of LPS and cytokines on hepatic fatty acid synthesis in LPS-sensitive C3H/OuJ mice and in LPS-resistant C3H/HeJ mice, whose macrophages are defective in the ability to produce tumor necrosis factor (TNF) and IL-1 in response to LPS. HeJ mice were 16-fold less sensitive than OuJ mice to the lipogenic effect of LPS. In OuJ mice, 10 micrograms of LPS caused a maximal increase in hepatic lipogenesis (3.86 +/- 0.41-fold), whereas in HeJ mice the maximal increase was only 1.79 +/- 0.32-fold after 100 micrograms of LPS. This lipogenic response paralleled the decreased ability of LPS to increase hepatic and splenic levels of mRNAs for TNF and IL-1 and serum levels of TNF in HeJ mice. In contrast, the maximal effect of TNF on lipogenesis was greater and the sensitivity to TNF was increased 2.4-fold in HeJ mice compared to OuJ mice. Administration of IFN-gamma before LPS in HeJ mice had no effect on IL-1 mRNA, but partially restored the LPS-induced increase in hepatic and splenic mRNA for TNF and serum TNF levels, which may account for the partial restoration of sensitivity to the lipogenic effect of LPS after IFN-gamma treatment. These results indicate that cytokines produced by mononuclear leukocytes mediate the lipogenic effects of LPS.
Animals↗
Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice.
The disruption of the cutaneous permeability barrier results in metabolic events that ultimately restore barrier function. These include increased epidermal sterol, fatty acid, and sphingolipid synthesis, as well as increased epidermal DNA synthesis. Because tumor necrosis factor (TNF) and other cytokines are known products of keratinocytes and have been shown to modulate lipid and DNA synthesis in other systems, their levels were examined in two acute models and one chronic model of barrier perturbation in hairless mice. Acute barrier disruption with acetone results in a 72% increase in epidermal TNF 2.5 h after treatment, as determined by Western blotting. Furthermore, epidermal TNF mRNA was elevated ninefold over controls 2.5 h after acetone treatment. This elevation in TNF mRNA was maximal at 1 h after acetone, and decreased to control levels by 8 h. After tape stripping, a second acute model of barrier disruption that avoids application of potentially toxic chemicals, TNF mRNA was elevated fivefold over controls at 2.5 h. Moreover, the mRNA levels for epidermal IL-1 alpha, IL-1 beta, and granulocyte macrophage-colony-stimulating factor (GM-CSF) also were elevated several-fold over controls, after either acetone treatment or tape stripping, but their kinetics differed. GM-CSF mRNA reached a maximal level at 1 h after acetone, while IL-1 alpha and IL-1 beta were maximal at 4 h after treatment. In contrast, mRNAs encoding IL-6 and IFN gamma were not detected either in control murine epidermis or in samples obtained at various times after tape stripping or acetone treatment. The relationship of the cytokine response to barrier function is further strengthened by results obtained in essential fatty acid deficient mice. In this chronic model of barrier perturbation mRNA levels for epidermal TNF, IL-1 alpha, IL-1 beta, and GM-CSF were each elevated several-fold over controls. These results suggest that epidermal cytokine production is increased after barrier disruption and may play a role in restoring the cutaneous permeability barrier.
Animals↗
Ontogeny of the epidermal barrier to water loss in the rat: correlation of function with stratum corneum structure and lipid content.
The mammalian epidermal permeability barrier is provided by highly hydrophobic lipids forming multiple membrane bilayers within the extracellular domains of the outer, cornified cell layers. To characterize the critical events associated with barrier maturation, we correlated the emergence of a competent barrier to transepidermal water loss with development of the lamellar body secretory system, the organization of stratum corneum membrane bilayers, and the lipid composition of these membranes in the perinatal rat. Whereas pups of 19 d estimated gestational age had no measurable barrier (transepidermal water loss greater than 10 mg/cm2/h), by 21 d the barrier was well established (mean transepidermal water loss 0.41 mg/cm2/h). Development of a functional barrier correlated with increasing thickness of the stratum corneum, as well as with development of a membrane pattern of lipid deposition, visualized with the hydrophobic fluorescent probe nile red. At 19 d estimated gestational age, the stratum corneum intercellular domains exhibited an abundance of secreted lamellar body contents, but they were not organized into basic bilayer unit structures. Lamellar unit structures became evident by 20 d and extended throughout the stratum corneum interstices by 22 d (term). The quantity of lipid in isolated stratum corneum increased significantly between 19 and 20 d (34.08 versus 50.08 mean micrograms lipid/cm2, respectively; p less than 0.02) and still further between 20 and 21 d estimated gestational age (74.49 micrograms lipid/cm2; p less than 0.001). This increase was due to progressive accumulation of neutral lipids, particularly cholesterol, as well as nonpolar ceramides, as shown by thin-layer chromatography/scanning densitometry. These studies imply that in the development of cutaneous barrier function in the fetal rat both the generation of sufficient quantities of hydrophobic lipids and the organization of these lipids into bilayer unit structures are required.
Age Factors↗
Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis.
Multiple cytokines induce a number of alterations in lipid metabolism which can produce hyperlipidemia. Recent studies have demonstrated that tumor necrosis factor (TNF) increases lipolysis, resulting in an increase in circulating FFA levels, which stimulates hepatic triglyceride production, thereby contributing to the hyperlipidemia induced by TNF. In the present investigation we have determined the effects of a variety of cytokines on lipolysis in cultured 3T3-F442A adipocytes. TNF increased lipolysis approximately 3-fold with a maximal effect at 100 ng/ml and a half-maximal increase at 5-10 ng/ml. This increase was first observed 8 h after incubation with TNF. Interleukin-1 (IL-1) and interferon-alpha (IFN), -beta, and -gamma also stimulated lipolysis in cultured adipocytes. The half-maximal increase in lipolysis occurred at approximately 10 ng/ml IL-1, 5 ng/ml IFN alpha, 10 ng/ml IFN beta, and 8 ng/ml of IFN gamma. Maximal lipolysis was observed at approximately 100 ng/ml for each of these cytokines, with the exception of IFN beta, for which maximal stimulation was observed at 1000 ng/ml. Neither platelet-activating factor nor IL-6 stimulated lipolysis; therefore, it is unlikely that these compounds mediate the increase in lipolysis induced by cytokines. However, indomethacin, a well known inhibitor of prostaglandin synthesis, prevented the increase in lipolysis induced by TNF, IL-1, IFN alpha, IFN beta, or IFN gamma. Indomethacin did not affect basal lipolysis or the acute stimulation of lipolysis induced by epinephrine. These results demonstrate that multiple cytokines can increase lipolysis and that this increase is mediated by cytokine-induced stimulation of prostaglandin synthesis.
3T3 Cells↗
In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis.
The host response to infection and cancer produces disturbances in fatty acid (FA) oxidation and ketogenesis. Interferons (IFNs) stimulate lipolysis in cultured adipocytes. Since FA mobilization is a major stimulus for ketogenesis, we studied the effect of IFN alpha and IFN gamma on lipolysis and ketogenesis in intact mice. Both IFNs acutely stimulated lipolysis; however, their effects on ketogenesis differed. INF gamma increased serum and hepatic ketone body levels in parallel to its effect on serum FFA, whereas IFN alpha exerted a biphasic effect on ketogenesis. At low doses, IFN alpha increased serum and hepatic ketone body levels, whereas at higher doses, this ketogenic effect was abolished. To determine the mechanism of the biphasic response, we studied the effect of IFN alpha on hepatic malonyl-coenzyme-A (malonyl-CoA), the first committed intermediate in FA synthesis and an inhibitor of FA oxidation and ketogenesis. At low doses, IFN alpha had no effect on malonyl-CoA; however, higher doses of IFN alpha significantly increased malonyl-CoA levels, which could counterbalance its mobilization of FFA. In contrast, INF gamma had little effect on malonyl-CoA, and hence, the FA oxidation was not opposed. By using phenylisopropyladenosine to block IFN-induced lipolysis, we found that in the absence of increased FA flux, INF gamma did not exert a ketogenic effect. However, when IFN alpha-induced lipolysis was blocked, the higher doses of IFN alpha that raise malonyl-CoA levels were antiketogenic. These data suggest that both IFNs exert a ketogenic effect by stimulating lipolysis, but at higher doses the ketogenic effect of IFN alpha is counteracted by its effect on hepatic FA synthesis.
3-Hydroxybutyric Acid↗
Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
Infection causes disturbances in lipid metabolism that may be mediated by cytokines. Therefore we studied plasma lipids, lipoproteins, triglyceride (TG) metabolism, and serum cytokines in three groups: patients with the acquired immunodeficiency syndrome (AIDS) without active secondary infection, patients with evidence of human immunodeficiency virus infection but without clinical AIDS (HIV+), and controls. Plasma TGs and FFA were increased in AIDS, while plasma cholesterol, high density lipoprotein (HDL) cholesterol, apolipoprotein-A-1 (Apo-A-1), low density lipoprotein (LDL) cholesterol, and Apo-B-100 levels were decreased. Increased TG levels in AIDS were primarily due to increases in very low density lipoprotein of normal composition; in addition, LDL and HDL were TG enriched. In HIV+, TGs and FFA were not increased, but total cholesterol, HDL cholesterol, Apo-A-1, and Apo-B-100 were significantly decreased. Interferon-alpha (IFN alpha) and C-reactive protein levels were increased in AIDS, but tumor necrosis factor and haptoglobin levels were not. There was a significant correlation between plasma TGs and IFN alpha levels (r = 0.477; P less than 0.01), but not between TGs and tumor necrosis factor, C-reactive protein, haptoglobin, or P-24 antigen. In addition, there was no relationship between circulating IFN alpha levels and plasma cholesterol, HDL cholesterol, Apo-A-1, LDL cholesterol, Apo-B-100, or FFA. TG clearance time and postheparin lipase were significantly decreased in AIDS and HIV+. There was a strong correlation between serum IFN alpha levels and TG clearance time in AIDS and HIV+ (r = 0.783; P less than 0.001). In summary, decreases in cholesterol and cholesterol containing lipoproteins (including HDL) in both AIDS and HIV+ precede the appearance of hypertriglyceridemia and are not related to IFN alpha or TG levels. Our data raise the possibility that with development of AIDS, subsequent increases in IFN alpha may contribute to increases in plasma TG levels in part by decreasing the clearance of TG.
Acquired Immunodeficiency Syndrome↗
Role of cytokines in inducing hyperlipidemia.
Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and alpha-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and alpha-, beta-, and gamma-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗