Biomedical subjects

J K Shigenaga

Publications and source records attributed to J K Shigenaga.

At least 19 recordsLinked to original sources

PubMed2000

The acute phase response is associated with retinoid X receptor repression in rodent liver.

The acute phase response (APR) is associated with decreased hepatic expression of many proteins involved in lipid metabolism. The nuclear hormone receptors peroxisome proliferator-activated receptor alpha (PPARalpha) and liver X receptor (LXR) play key roles in regulation of hepatic lipid metabolism. Because heterodimerization with RXR is crucial for their action, we hypothesized that a decrease in RXR may be one mechanism to coordinately down-regulate gene expression during APR. We demonstrate that lipopolysaccharide (LPS) induces a rapid, dose-dependent decrease in RXRalpha, RXRbeta, and RXRgamma proteins in hamster liver. Maximum inhibition was observed at 4 h for RXRalpha (62%) and RXRbeta (50%) and at 2 h for RXRgamma (61%). These decreases were associated with a marked reduction in RXRalpha, RXRbeta, and RXRgamma mRNA levels. Increased RNA degradation is likely responsible for the repression of RXR, because LPS did not decrease RXRbeta and RXRgamma transcription and only marginally inhibited (38%) RXRalpha transcription. RXR repression was associated with decreased LXRalpha and PPARalpha mRNA levels and reduced RXR x RXR, RXR x PPAR and RXR x LXR binding activities in nuclear extracts. Furthermore, LPS markedly decreased both basal and Wy-14,643-induced expression of acyl-CoA synthetase, a well characterized PPARalpha target. The reduction in hepatic RXR levels alone or in association with other nuclear hormone receptors could be a mechanism for coordinately inhibiting the expression of multiple genes during the APR.

Acute-Phase Reaction↗

PubMed1999

Endotoxin and interleukin-1 decrease hepatic lipase mRNA levels.

The acute phase response induces a multitude of changes in lipoprotein metabolism including hypertriglyceridemia, triglyceride enriched LDL, and decreased HDL levels accompanied by changes in HDL composition including increased free cholesterol and triglycerides and a decrease in esterified cholesterol. Here we demonstrate that endotoxin (LPS) induces a 56% decrease in hepatic lipase activity in liver and a 45% decrease in hepatic lipase activity in post heparin plasma in Syrian hamsters. LPS treatment also produces a marked decrease in hepatic lipase mRNA levels in the liver. Half maximal reduction in hepatic lipase mRNA levels occurred at approximately 0.2 microg LPS/100 g BW with a maximal decrease at 1.0 microg/100 g BW ( > 90% decrease), indicating that inhibition of hepatic lipase is a sensitive host response to LPS. Additionally, IL-1 produced a marked decrease in hepatic lipase mRNA levels while TNF had no effect. Moreover, IL-1 treatment of HepG2 cells in vitro also decreased hepatic lipase mRNA levels suggesting that IL-1 can directly regulate hepatic lipase expression in liver cells. LPS decreased hepatic lipase mRNA levels in control as well as IL-1 type 1 receptor deficient mice indicating that IL-1 action is not absolutely essential and that several cytokines and/or small molecular mediators can regulate hepatic lipase during the acute phase response. The LPS and IL-1 induced decrease in hepatic lipase could have several consequences including decreasing the clearance of triglyceride rich lipoprotein particles and producing an increase in triglyceride rich HDL. The decrease in hepatic lipase activity and mRNA levels may be part of a series of coordinated changes in lipoprotein metabolism that occur during the acute phase response. These changes may be initially beneficial to the host but if present for an extended period may be proatherogenic.

Acute-Phase Reaction↗

PubMed1999

Plasma platelet-activating factor acetylhydrolase activity in human immunodeficiency virus infection and the acquired immunodeficiency syndrome.

Platelet-activating factor (PAF) acetylhydrolase (PAF-AH) catalyzes the hydrolysis of PAF, a mediator of inflammation, as well as other biologically active oxidized phospholipids. In humans, plasma PAF-AH activity is bound to low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Higher levels of plasma PAF-AH activity have been found in a variety of diseases, and are thought to be a defense mechanism against the toxic effects of PAF and oxidized phospholipids. We studied plasma PAF-AH activity in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), a disease characterized by chronic HIV infection and a systemic host response. Plasma PAF-AH activity was significantly greater in AIDS patients compared with control subjects (25.2 +/- 2.0 v 17.0 +/- 0.8 nmol/min/mL, P < .001). The higher levels of plasma PAF-AH activity were found in LDL (28.2 +/- 2.2 v 18.3 +/- 1.0 nmol/min/mL for AIDS v controls, respectively, P = .0005), but not in HDL. Plasma PAF-AH activity in AIDS correlated with circulating interferon alfa (r = .575, P = .005) and plasma triglycerides (r = .556, P < .0025). The presence of secondary infection in AIDS did not significantly change plasma PAF-AH activity. The initiation of a new antiretroviral regimen with either a protease inhibitor or the nucleoside analog lamivudine did not significantly decrease plasma PAF-AH activity, despite successful suppression of HIV RNA levels. Plasma PAF-AH activity may be a sensitive marker of the host response to infection, and the higher levels of plasma and LDL-associated PAF-AH activity in patients with HIV infection and AIDS may be a physiological response to protect the host against oxidative injury from PAF and oxidized phospholipids.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1999

Lipoproteins inhibit macrophage activation by lipoteichoic acid.

Regulation of lipid metabolism during infection is thought to be part of host defense, as lipoproteins neutralize endotoxin (LPS) and viruses. Gram-positive infections also induce disturbances in lipid metabolism. Therefore, we investigated whether lipoproteins could inhibit the toxic effects of lipoteichoic acid (LTA), a fragment of gram-positive bacteria. LTA activated RAW264.7 macrophage cells, stimulating production of tumor necrosis factor (TNF) in a dose-dependent matter, but produced less TNF than that seen after LPS activation. High density (HDL) or low density lipoprotein (LDL) alone inhibited the ability of LPS to stimulate TNF production, but had little effect on the activation by LTA. When a maximally effective dose of LTA was mixed with lipoproteins and 10% lipoprotein-depleted plasma (LPDP), the ability of LTA to stimulate macrophage production of TNF was inhibited. HDL, LDL, and the synthetic particle, Soyacal, when mixed with LPDP, were able to inhibit the ability of LTA to activate macrophages. Lipopolysaccharide-binding protein (LBP) substituted for LPDP in catalyzing lipoprotein neutralization of LTA by HDL. Antibody to LBP inhibited the ability of LPDP to induce LTA neutralization by HDL.Thus, lipoproteins can prevent macrophage activation by fragments from both gram-positive and gram-negative microorganisms.-Grunfeld, C., M. Marshall, J. K. Shigenaga, A. H. Moser, P. Tobias, and K. R. Feingold. Lipoproteins inhibit macrophage activation by lipoteichoic acid.

Animals↗

PubMed1998

Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin.

Alterations in triglyceride and cholesterol metabolism often accompany inflammatory diseases and infections. We studied the effects of endotoxin (lipopolysaccharide [LPS]) and cytokines on hepatic sphingolipid synthesis, activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme in sphingolipid synthesis, and lipoprotein sphingolipid content in Syrian hamsters. Administration of LPS induced a 2-fold increase in hepatic SPT activity. The increase in activity first occurred at 16 hours, peaked at 24 hours, and was sustained for at least 48 hours. Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at approximately 0.3 microg LPS/100 g body weight. LPS increased hepatic SPT mRNA levels 2-fold, suggesting that the increase in SPT activity was due to an increase in SPT mRNA. LPS treatment also produced 75% and 2.5-fold increases in hepatic sphingomyelin and ceramide synthesis, respectively. Many of the metabolic effects of LPS are mediated by cytokines. Interleukin 1 (IL-1), but not tumor necrosis factor, increased both SPT activity and mRNA levels in the liver of intact animals, whereas both IL-1 and tumor necrosis factor increased SPT mRNA levels in HepG2 cells. IL- produced a 3-fold increase in SPT mRNA in HepG2 cells, and the half-maximal dose was 2 ng/mL. IL-1 also increased the secretion of sphingolipids into the medium. Analysis of serum lipoprotein fractions demonstrated that very low density lipoprotein, intermediate density lipoprotein, and low density lipoprotein isolated from animals treated with LPS contained significantly higher amounts of ceramide, glucosylceramide, and sphingomyelin. Taken together, these results indicate that LPS and cytokines stimulate hepatic sphingolipid synthesis, which results in an altered structure of circulating lipoproteins and may promote atherogenesis.

Acyltransferases↗

PubMed1998

Regulation of microsomal triglyceride transfer protein mRNA expression by endotoxin and cytokines.

We studied the effect of endotoxin (LPS), and cytokines (TNF, IL-1, and IL-6) on hepatic microsomal triglyceride transfer protein (MTP) mRNA levels in vivo in Syrian hamsters and in vitro in HepG2 cells. LPS, interleukin-1 (IL-1), and to a lesser extent tumor necrosis factor (TNF) significantly decreased MTP mRNA levels in hamster liver. These effects required several hours. Furthermore, IL-1 and IL-6 significantly decreased MTP mRNA levels in HepG2 cells. This decrease appeared soon after IL-1 administration (8 h) and at very low doses (0.1 ng/ml). MTP activity and protein levels of the large subunit of MTP also decreased modestly in HepG2 cells with prolonged cytokine treatment. IL-1 reduced the expression of an MTP promoter luciferase construct to a similar degree as seen with MTP mRNA, indicating that transcriptional regulation plays a major role in the decrease of MTP gene expression. Deletional analysis of the MTP promoter identified the region -121 to -88 bp upstream to the coding sequence as the site of the negative regulation by IL-1. This region contains an insulin response element (IRE), activating protein 1 (AP-1), hepatic nuclear factor 1 (HNF-1) and hepatic nuclear factor 4 (HNF-4) consensus sequences; mutations of the IRE and HNF-4 sites did not affect the response to IL-1. In contrast, mutating AP-1 or HNF-1 sites led to a marked decrease in basal expression and the loss of the IL-1 effect, suggesting that an intact AP-1 and/or HNF-1 regulatory element are crucial for the IL-1 regulation of MTP gene expression. However, prolonged incubation with IL-1 did not alter HepG2 apolipoprotein B secretion suggesting that MTP mRNA down-regulation does not contribute significantly to the cytokine-induced effects on lipid metabolism.

Animals↗

PubMed1997

Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic squalene synthase activity, protein, and mRNA levels in Syrian hamsters.

Recent studies have shown that endotoxin (LPS) administration to Syrian hamsters markedly increased hepatic HMG-CoA reductase activity, protein mass, and mRNA levels, but only produced a modest increase in hepatic cholesterol synthesis, suggesting that LPS may also influence other key enzymes involved in the regulation of cholesterol metabolism. In the present study, we have examined the effect of LPS and cytokines on the activity, protein mass, and mRNA level of squalene synthase, which is the first committed enzyme in cholesterol biosynthesis and is located at a branch point in the mevalonate pathway. Our results demonstrate that LPS administration produces a marked decrease in the mRNA levels of squalene synthase. This decrease in squalene synthase mRNA occurred very rapidly (90 min after LPS) and required relatively small doses of LPS (1 microg/100 gm body weight). LPS also significantly decreased squalene synthase activity and protein mass. Finally, LPS produced a marked decrease in squalene synthase mRNA, activity, and protein levels when the basal levels of squalene synthase expression were increased 4-fold by prior treatment with bile acid binding resin, colestipol. Tumor necrosis factor and interleukin-1, which mediate many of the metabolic effects of LPS, also decreased hepatic squalene synthase activity and mRNA levels. Taken together, our results suggest that the discordant regulation of HMG-CoA reductase and squalene synthase during the host response to infection and inflammation may have substantial effects on the regulation of substrate flux into the non-sterol pathways of mevalonate metabolism.

Animals↗

PubMed1996

Serum leptin levels in the acquired immunodeficiency syndrome.

Leptin, a hormone that is secreted by adipose tissue in proportion to fat stores, regulates energy balance and appetite. Recently, tumor necrosis factor and interleukin-1, cytokines that regulate the host response to infection, have been shown to acutely increase leptin levels, raising the possibility that leptin could mediate the anorexia of some infections. We measured leptin levels in patients with the acquired immunodeficiency syndrome and found that leptin levels were not increased relative to body fat in patients who were anorectic, were losing weight, or had a history of weight loss. Furthermore, leptin levels were not increased during secondary infection, suggesting that elevations in leptin do not play a key role in the anorexia of infections associated with acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Role for circulating lipoproteins in protection from endotoxin toxicity.

Previous studies have shown that endotoxin (lipopolysaccharide [LPS])-induced death can be prevented by preincubating LPS with lipoproteins in vitro or by infusing large quantities of lipids into animals prior to LPS administration. In the present study we determined whether physiological levels of lipids also provide protection. Serum lipid levels were decreased by two different mechanisms: administration of 4-aminopyrolo-(3,4-D)pyrimide, which prevents the hepatic secretion of lipoproteins, and administration of pharmacological doses of estradiol, which increases the number of hepatic low-density lipoprotein receptors, leading to increased lipoprotein clearance. In both hypolipidemic models, LPS-induced mortality is markedly increased compared with that of controls with normal serum lipid levels. In both hypolipidemic models, administration of exogenous lipoproteins, which increase levels of serum lipids into the physiological range, reduces the increased mortality to levels similar to that seen in normal animals. In normal lipidemic animals, 63% of 125I-LPS in plasma is associated with lipoproteins, where it would not be capable of stimulating cytokine production. In contrast, in hypolipidemic animals, very little LPS (12 to 17%) is associated with lipoproteins. Rather, more LPS is in the lipoprotein-free plasma compartment, where it could exert biological effects. In both hypolipidemic models, LPS produces a greater increase in serum tumor necrosis factor levels than it does in controls (three- to fivefold increase), and administration of exogenous lipoproteins prevents this increase. Cytokines, in particular tumor necrosis factor, are responsible for most of the toxic effects of LPS. These data provide evidence that physiological levels of serum lipids protect animals from LPS toxicity. Thus, lipoproteins, in addition to playing a role in lipid transport, may have protective functions. Moreover, as part of the immune response, cytokine-induced increases in serum lipid levels may play a role in host defense by decreasing the toxicities of biological and chemical agents.

Adenine↗

PubMed1995

Endotoxin induces parathyroid hormone-related protein gene expression in splenic stromal and smooth muscle cells, not in splenic lymphocytes.

PTH-related protein (PTHrP), the peptide that is responsible for most cases of hypercalcemia of malignancy, is also produced under normal circumstances by a variety of tissues. Its role and regulation at these sites are not well understood. Recently, we have shown that PTHrP is induced in the spleen during the host response to endotoxin (LPS) and that tumor necrosis factor (TNF) is a major mediator of this effect. Given the large body of in vitro evidence suggesting that PTHrP can be produced by lymphocytes and act in an autocrine loop to alter their function, studies were undertaken to determine whether lymphocytes were the cells responsible for PTHrP production in the spleen. Both constitutive and LPS-induced PTHrP messenger RNA (mRNA) levels were the same in mice lacking mature T cells (nude mice) and in mice lacking natural killer (NK) cells (due to pretreatment with antibody against NK 1.1) compared to levels in normal mice, suggesting that neither mature T cells nor NK cells were the splenic source of PTHrP. Even scid mice that lack functioning T and B cells responded to TNF with the induction of splenic PTHrP mRNA levels comparable to those in control mice. Localization of PTHrP mRNA in subfractions of rat spleens after in vivo treatment with LPS confirmed the results of the murine studies; PTHrP mRNA was barely detectable in the lymphocyte-rich single cell fraction of the spleen. In contrast, the stromal fraction of the spleen was enriched with PTHrP mRNA both in the basal state and in response to LPS. A similar pattern of distribution was seen for interleukin-6; LPS only increased mRNA levels of this TNF-inducible cytokine in the splenic stroma. In addition, mRNA for the PTH/PTHrP receptor, which decreased in response to LPS, colocalized with PTHrP mRNA in the stromal fraction of the spleen. Immunohistochemical studies identified PTHrP in two populations of splenic cells: 1) smooth muscle cells located in the splenic capsule and trabeculae and 2) a subpopulation of stromal cells located in the red pulp of the spleen, primarily in a subcapsular distribution. Consistent with the localization of PTHrP mRNA, lymphocytes in the white pulp of the spleen did not stain for PTHrP.

Animals↗

PubMed1995

Discordant regulation of proteins of cholesterol metabolism during the acute phase response.

Recent studies have shown that the administration of endotoxin (LPS) and cytokines to Syrian hamsters increases serum cholesterol levels, hepatic cholesterol synthesis, and the activity, protein levels, and mRNA levels of hepatic HMG-CoA reductase. Despite the greater than 10-fold increase in HMG-CoA reductase mRNA levels, LPS had only minimal effects on hepatic LDL receptor mRNA levels. In the present study, we demonstrate that LPS increases the transcription rate in the liver of HMG-CoA reductase mRNA approximately 4- to 5-fold without affecting LDL receptor mRNA transcription. Most stimuli that regulate HMG-CoA reductase and LDL receptor mRNA levels also regulate, in parallel, HMG-CoA synthase and farnesyl pyrophosphate (FPP) synthetase. However, in chow-fed animals, LPS and cytokines (TNF, IL-1, TNF + IL-1) increased hepatic HMG-CoA reductase mRNA levels without increasing LDL receptor, HMG-CoA synthase, or FPP synthetase mRNA levels. The feeding of cholesterol or bile resin binders regulates the mRNA levels of HMG-CoA reductase, LDL receptor, HMG-CoA synthase, and FPP synthetase. In both cholesterol- and colestipol-fed animals, LPS increased HMG-CoA reductase mRNA levels while either decreasing or causing minimal increases in the mRNA levels of the other proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗

PubMed1995

Endotoxin and TNF lead to reduced plasma LCAT activity and decreased hepatic LCAT mRNA levels in Syrian hamsters.

Endotoxin (LPS) administration, which mimics infection, stimulates the production of many cytokines, including TNF, that are thought to mediate the alterations in lipid metabolism that occur during infection. The aims of this study were to determine the effect of LPS or TNF administration on plasma LCAT activity and hepatic LCAT mRNA levels in Syrian hamsters. Plasma LCAT activity was decreased 8 h after LPS administration, reached a maximum level of inhibition at 16 h which persisted for at least 24 h, at which time the activity was 53% of control values. The decrease in plasma LCAT activity was first seen at an LPS dose of 0.01 microgram/100 g body weight and reached a maximum at 50-100 micrograms/100 g body weight. The ratio of free to esterified cholesterol in the plasma increased in the LPS-treated animals. Moreover, LPS administration decreased LCAT mRNA levels in the liver. The decrease in hepatic LCAT mRNA levels preceded the decrease in plasma LCAT activity. Additionally, TNF treatment (16.7 micrograms/100 g body weight) decreased plasma LCAT activity by 35% and LCAT mRNA levels in the liver by 60% 16 h after administration. Lastly, in cultured rat H35 hepatocytes, TNF decreased LCAT mRNA levels in the liver by 60% 16 h after administration. Lastly, in cultured rat H35 hepatocytes, TNF decreased LCAT mRNA levels by 50% with a 1/2 maximal dose of approximately 1 ng/ml. Thus, plasma LCAT activity and hepatic mRNA levels are decreased by LPS or TNF treatment. LCAT is a member of a group of proteins that affect lipid and lipoprotein metabolism whose levels are altered during the host's acute phase response.

Animals↗

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↗

PubMed1993

Endotoxin increases parathyroid hormone-related protein mRNA levels in mouse spleen. Mediation by tumor necrosis factor.

Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in malignancy. However, the role and regulation of PTHrP in normal physiology is just beginning to be explored. PTHrP is found in the spleen and has several other features common to cytokines. Since endotoxin (LPS) causes many of its effects indirectly by inducing cytokines, studies were undertaken to determine whether LPS might also induce splenic PTHrP expression. LPS (100 ng/mouse) increased splenic PTHrP mRNA levels 3.6-fold in C3H/OuJ mice. This effect was maximal at 2 h and returned to baseline by 4 h. PTHrP peptide levels also increased 3.3-fold in splenic extracts in response to LPS (1 microgram/mouse). Murine TNF-alpha and human IL-1 beta, cytokines that mediate many of the effects of LPS, also increased splenic PTHrP mRNA levels. LPS-resistant C3H/HeJ mice, which produce minimal amounts of TNF and IL-1 in response to LPS, were resistant to LPS induction of splenic PTHrP mRNA, while TNF-alpha and IL-1 beta readily increased PTHrP mRNA levels in C3H/HeJ mice. Anti-TNF antibody blocked LPS induction of splenic PTHrP mRNA in C3H/OuJ mice by 68%, indicating that TNF is a mediator of the LPS induction of PTHrP levels. In contrast, an IL-1 receptor antagonist (IL-1ra) was ineffective. The increase in PTHrP in the spleen during the immune response suggests that PTHrP may play an important role in immune modulation, perhaps by mediating changes in lymphocyte proliferation and/or function.

Animals↗

PubMed1992

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↗

PubMed1992

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↗

PubMed1992

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↗

PubMed1992

Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.

Hyperlipidemia frequently accompanies infectious diseases and may be due to increases in lipoprotein production or decreases in lipoprotein clearance. The administration of endotoxin (LPS) has been used to mimic infection and prior studies demonstrate that LPS produces hypertriglyceridemia. In the present study in rodents, the dose of LPS necessary to induce hyperlipidemia was orders of magnitude less than that necessary to induce shock and death. As little as 10 ng/100 g body weight induced hypertriglyceridemia and this increase in serum triglyceride levels occurred rapidly (78% increase at 2 h). At high doses of LPS (50 micrograms/100 g body weight), the clearance of triglyceride-rich lipoproteins was decreased. At low doses of LPS (100 ng/100 g body weight), triglyceride clearance was not altered but the hepatic secretion of triglyceride was increased. Low dose LPS stimulated hepatic de novo fatty acid synthesis and lipolysis, both of which provided a source of fatty acids for the increase in hepatic triglyceride production. High dose LPS did not increase hepatic fatty acid synthesis or peripheral lipolysis, and hepatic triglyceride secretion was not stimulated. Thus, low dose LPS produces hypertriglyceridemia by increasing hepatic lipoprotein production, while high dose LPS produces hypertriglyceridemia by decreasing lipoprotein catabolism. Administration of anti-tumor necrosis factor (TNF) antibodies or interleukin 1 (IL-1) receptor antagonist did not prevent the increase in serum triglyceride levels induced by LPS. However, anti-TNF antibodies and interleukin 1 receptor antagonist (IL-1ra) blocked the increase in serum triglycerides induced by TNF or IL-1, respectively. These data suggest that neither of these cytokines is absolutely required for the increase in serum triglycerides induced by LPS, raising the possibility that other cytokines, small molecular mediators, or LPS itself may play a crucial role.

Animals↗