Biomedical subjects

A H Moser

Publications and source records attributed to A H Moser.

At least 55 records · Page 3Linked 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

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↗

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

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↗

PubMed1993

Preservation of permeability barrier ontogenesis in the intrauterine growth-retarded fetal rat.

The epidermal permeability barrier is provided by intercellular lipids forming multiple membrane bilayers in the stratum corneum. In the fetal rat, the barrier to transepidermal water loss forms during the 20th d of gestation and is accompanied by 1) increasing stratum corneum thickness; 2) increasing stratum corneum lipid content, particularly nonpolar ceramide and cholesterol content; and 3) the formation of lamellar unit structures throughout the stratum corneum interstices. In this report, we demonstrate that among pups of 20 d gestational age increasing barrier competence is correlated with increasing fetal weight. It has been previously demonstrated that fetal rats subjected to intrauterine growth retardation (IUGR) exhibit a thinner stratum corneum and decreased content of differentiation-specific epidermal structural proteins. To determine whether IUGR fetal rats also exhibit immaturity of barrier function and the barrier membrane system, maternal rats underwent unilateral uterine vessel ligation on d 17 or 18 of gestation and IUGR and control littermates were harvested on d 20, 21, or 22 of gestation for determination of transepidermal water loss. Despite significant somatic growth retardation and a thinner stratum corneum, barrier function in IUGR fetal rats did not significantly differ from that in control littermates at any gestational age. In both IUGR and control fetal rat epidermis at 21 d gestational age, lipids were deposited in a membrane pattern as visualized by nile red fluorescence microscopy and formed lamellar unit membrane structures throughout the stratum corneum intercellular domains as observed by electron microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice.

The host response to infection is frequently accompanied by changes in cholesterol and triglyceride (TG) metabolism. To determine the role of cytokines in mediating these changes, we studied the effects of endotoxin (LPS), tumor necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1) on cholesterol and TG metabolism in C57Bl/6 (LPS-sensitive) mice and in C3H/HeJ (LPS-resistant) mice whose macrophages do not produce TNF and IL-1 in response to LPS. Sixteen hours after administration, LPS (1 micrograms/mouse) produced a 41% increase in serum cholesterol and a 62% increase in serum TG levels in C57Bl/6 mice whereas a 100-fold higher dose of LPS did not have a significant effect in C3H/HeJ mice. LPS (1 microgram/mouse) also produced a 8.6-fold increase in hepatic cholesterol synthesis and a 2.7-fold increase in hepatic fatty acid synthesis in C57Bl/6 mice but had no effect in C3H/HeJ mice. This suggests that macrophage produced cytokines such as TNF and IL-1 may be involved in mediating these effects of LPS. Additionally, LPS also increased the activity of hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. As seen with LPS, TNF and IL-1 also increased serum cholesterol and TG levels in C57Bl/6 mice. Moreover, TNF and IL-1 produced a 2.3- and 2.1-fold increase in hepatic HMG-CoA reductase activity, respectively. Finally, pretreatment of mice with anti-TNF antibodies, but not with an IL-1 receptor antagonist, blocked the effect of LPS on serum cholesterol and TG levels, hepatic cholesterol and fatty acid synthesis, and hepatic HMG-CoA reductase activity. These results suggest that whereas both TNF and IL-1 mimic the effects of LPS on cholesterol and TG metabolism, TNF may be the in vivo mediator of these late effects of LPS in mice.

Animals↗

PubMed1993

Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.

Infection and inflammation increase serum triglyceride and cholesterol levels in rodents and rabbits. Endotoxin (LPS) has been used as a model of infection and its effects on triglyceride metabolism have been previously characterized. In the present study we demonstrate that both low (100 ng/100 g body weight) and high dose (100 micrograms/100 g body weight) LPS increase serum cholesterol levels in hamsters. The increase in serum cholesterol is first observed 16 h after LPS and persists for at least 24 h. This increase is primarily due to an increase in low density lipoprotein (LDL) cholesterol. High density lipoprotein (HDL) cholesterol levels decrease after LPS treatment. Both low and high dose LPS increase hepatic cholesterol synthesis (low dose 85%, high dose 205%) and total HMG-CoA reductase activity (low dose 2.97-fold, high dose 9.96-fold). However, the proportion of HMG-CoA reductase in the active form is reduced by LPS treatment. Additionally, the mass of HMG-CoA reductase protein in the liver, measured by Western blotting, is increased after LPS. Moreover, LPS increases hepatic HMG-CoA reductase mRNA levels (low dose 3.1-fold, high dose 14.2-fold). The increase in hepatic HMG-CoA reductase mRNA levels is first seen 4 h after LPS and persists for at least 24 h. In contrast, LPS had only minimal effects on hepatic LDL receptor protein and mRNA levels. These results suggest that LPS increases serum cholesterol levels by increasing hepatic cholesterol synthesis. LPS administration decreases apoE mRNA levels in the liver while having no effect on apoA-I mRNA levels. These results suggest that HMG-CoA reductase is a member of a group of hepatic proteins that are positively regulated by inflammatory stimuli (acute phase proteins) while apoE can be considered a negative acute phase protein in hamsters. It is possible that increases in hepatic HMG-CoA reductase provide cholesterol that allows for the increased production of lipoproteins and elevations in serum lipid levels that may be beneficial to the body's host defense.

Animals↗

PubMed1992

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↗

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

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↗

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↗

PubMed1991

Interleukin 4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin 1, and interleukin 6 but not by interferon-alpha.

Multiple cytokines stimulate hepatic lipogenesis in rodents. We have previously shown that lipogenic cytokines can be divided into 2 classes by their mechanism of action and their synergistic interactions. We now report the effects of interleukin 4, a cytokine known to inhibit the synthesis and action of other cytokines. Interleukin 4 by itself did not alter hepatic lipogenesis. However, interleukin 4 inhibited the characteristic stimulation of hepatic lipogenesis that is seen with tumor necrosis factor, interleukin 1, and interleukin 6. These 3 cytokines stimulate hepatic lipogenesis by the same mechanism, increasing hepatic levels of citrate, a key allosteric activator of acetyl CoA carboxylase, the rate-limiting enzyme of fatty acid synthesis. Interleukin 4 blocks the ability of tumor necrosis factor to increase hepatic citrate. In contrast, interleukin 4 does not block the stimulation of hepatic lipogenesis by interferon-alpha, a cytokine that increases hepatic lipogenesis by a mechanism other than increasing hepatic citrate levels. These results demonstrate that interleukin 4 can inhibit the metabolic action of selected cytokines, which provides strong support for our proposal that lipogenic cytokines operate through 2 distinct mechanisms of action and can therefore be divided into 2 separate classes based on their interactions. These results also emphasize the multiple relationships between the immune response and lipid metabolism.

Animals↗

PubMed1990

The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis.

Previous studies have demonstrated that tumor necrosis factor (TNF) acutely increases serum triglyceride levels and stimulates hepatic lipid synthesis. In this study, we determined the effects of TNF on serum lipid levels and hepatic lipid synthesis in animals whose diets and feeding conditions were varied to induce changes in baseline serum lipid levels and/or rates of hepatic lipid synthesis. In animals studied at both the nadir and peak of the diurnal cycle of hepatic lipid synthesis, TNF acutely increases serum triglyceride levels, stimulates hepatic fatty acid synthesis, and increases the quantity of newly synthesized fatty acids found in the serum. Similarly, in animals ingesting either high-sucrose or cholesterol-enriched diets, TNF induces the characteristic rapid increase in serum triglyceride levels, hepatic fatty acid synthesis, and quantity of labeled fatty acids in the serum. In animals fed a diet high in triglycerides, using either corn oil or lard, TNF stimulates hepatic fatty acid synthesis and increases the quantity of newly synthesized fatty acids in the serum, but serum triglyceride levels do not change. However, TNF inhibits gastric emptying, which results in a marked decrease in fat absorption in TNF-treated animals. It is likely that a decrease in the dietary contribution to serum triglyceride levels during high-triglyceride feeding counterbalances the increased hepatic contribution induced by TNF treatment. In animals fasted before TNF administration there was no acute change in either serum lipid levels, hepatic fatty acid synthesis, or the quantity of labeled fatty acids in the serum. Thus, TNF stimulates hepatic fatty acid synthesis and increases serum triglyceride levels under many diverse dietary conditions, suggesting that there is a strong linkage between the immune system and lipid metabolism that is independent of most dietary manipulations and may be of fundamental importance in the body's response to infection.

Animals↗

PubMed1990

Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production.

Tumor necrosis factor (TNF) induces hyperlipidemia in rodents by increasing hepatic triglyceride production. We now explore the mechanism of this increase. TNF does not increase phosphatidate phosphohydrolase, glycerolphosphate acyltransferase, or diacylglycerol acyltransferase, which are enzymes of triglyceride synthesis. Rather, TNF increases triglyceride production by providing increased fatty acids (FA) as substrate. In chow-fed rats, TNF increases plasma free fatty acids (FFA). The antilipolytic drug, phenylisopropyl adenosine (PIA), prevents the TNF-induced increase in plasma FFA and, most importantly, inhibits the TNF-induced increase in plasma triglycerides. Thus increased lipolysis with delivery of FA to liver contributes to TNF-induced hyperlipidemia in chow-fed animals. In contrast, in rats fed a high-sucrose diet, TNF causes hyperlipidemia without increasing plasma FFA, and PIA has no effect on TNF-induced increases in plasma triglycerides. However, in sucrose-fed rats, TNF markedly stimulates hepatic de novo FA synthesis, which provides FA. This diet determines the mechanism by which TNF stimulates hepatic triglyceride production. The use of multiple mechanisms to increase plasma triglycerides suggests that this TNF action plays an important role in the response to infection or inflammation.

Acyltransferases↗

PubMed1990

Evidence for two classes of cytokines that stimulate hepatic lipogenesis: relationships among tumor necrosis factor, interleukin-1 and interferon-alpha.

Tumor necrosis factor (TNF) increases serum triglycerides in rats by increasing de novo hepatic fatty acid synthesis and very low density lipoprotein production. We have recently shown that several other cytokines increase hepatic fatty acid synthesis in the mouse. We now explore the mechanism by which these cytokines increase de novo lipogenesis and the interactions between cytokines in fed mice. TNF administration results in increased hepatic levels of citrate, the primary allosteric activator of acetyl-CoA carboxylase, which is the major rate-limiting enzyme for fatty acid synthesis. The TNF-induced increase in citrate occurs within 15 min of administration, early enough to account for the acute rise in hepatic fatty acid synthesis seen by 30 min after TNF administration. IL-1, which also increases hepatic fatty acid synthesis, produces similar increases in hepatic citrate levels. In contrast, another potent stimulator of hepatic fatty acid synthesis, interferon-alpha (IFN alpha), has no effect on hepatic citrate levels. There were no acute effects of TNF or IL-1 on the activation state of acetyl-CoA carboxylase. A trend toward an increase in the activation state of acetyl-CoA carboxylase was seen after IFN alpha administration. Low doses of TNF and IL-1 given in combination show no synergy while maximal doses are not additive. In contrast, when a low dose of either TNF or IL-1 is combined with a low dose of IFN alpha, there is synergy in stimulating hepatic fatty acid synthesis. A maximal dose of TNF or IL-1 and a high dose of IFN alpha produce a further increase in hepatic fatty acid synthesis. These data support the concept that there are two classes of cytokines that stimulate hepatic fatty acid synthesis, those that can increase hepatic citrate levels and those that cannot.

Acetyl-CoA Carboxylase↗

PubMed1989

Persistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/cachectic effects in rats.

The administration of a single injection of tumor necrosis factor (TNF) produces a variety of acute and sustained biological effects, including hyperlipidemia, stimulation of hepatic lipogenesis, decreases in adipose tissue lipoprotein lipase activity, and anorexia with weight loss. Chronic administration of a fixed dose of TNF produces tachyphylaxis to the anorectic/cachectic effects of TNF. We now report that the hyperlipidemic effect of TNF persists during chronic TNF administration in the absence of any cachectic effect of TNF. Sprague-Dawley rats injected with TNF (250 micrograms/kg) show a significant decrease in weight over the next 24 h which can be accounted for by decreases in food and water intake accompanied by an increase in urine output. With subsequent daily injections of TNF, treated rats begin eating and rapidly regain weight. Hypertriglyceridemia persists for up to 10 days of daily injections of TNF. After three daily injections of TNF, no decreases were seen in lipoprotein lipase activity in a wide variety of tissues. De novo hepatic lipogenesis remained increased in TNF-treated animals after four daily injections, but by the fifth day hepatic lipogenesis returned to normal. After 5 days of TNF treatment the acute incorporation of labeled glycerol into serum triglycerides remained elevated. These data indicate that hyperlipidemia persists during multiple daily injections of TNF and that TNF induced hypertriglyceridemia is not inevitably linked to the syndrome of cachexia.

Animals↗