Biomedical subjects

W Doerrler

Publications and source records attributed to W Doerrler.

16 recordsLinked to original sources

PubMed1997

Abnormalities of apolipoprotein E in the acquired immunodeficiency syndrome.

Given the important role of apolipoprotein E (apoE) in triglyceride metabolism, we analyzed plasma levels and degree of sialylation of apoE in subjects with the acquired immunodeficiency syndrome (AIDS), a disorder accompanied by hypertriglyceridemia. Levels of apoE were significantly increased (1.84-fold) and correlated with plasma triglycerides (r = .663, P < .001) in AIDS. Subjects with AIDS and the apoE3/E2 phenotype showed the most prominent increases in both plasma triglyceride and apoE levels (3.4 and 2.2-fold over controls). Additionally, apoE from subjects with AIDS showed an increased amount of sialylation, compared with controls (34% increase in apoE3/E3 subjects). Increased sialylation correlated with the increase in apoE levels. In contrast, there was no increase in sialylation of apo C-III in AIDS. Thus, triglyceride levels in AIDS are influenced by apoE subtype and subjects with AIDS show changes in apoE structure.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms.

Previous studies have demonstrated that some cytokines induce a coordinate catabolic response in adipose cells which leads to decreased fat storage. The mechanisms by which cytokines cause these effects are unknown. The primary purpose of the present study was to determine the effects of TNF, IL-1, IFN-alpha and IFN-alpha on the mRNA levels of the key enzymes involved in fat metabolism in 3T3-F442A adipocytes. TNF, IL-1, IFN-alpha and IFN-gamma decreased lipoprotein lipase activity and increased lipolysis in adipocytes. TNF, IFN-alpha and IFN-gamma decreased fatty acid synthesis while IL-1 increased fatty acid synthesis. However, the cytokine effects on mRNA levels were not always consistent with the observed changes in activity and were unique for each cytokine. Specifically, while all cytokines decreased LPL activity, only TNF and IFN-gamma decreased LPL mRNA levels. In addition, while TNF, IFN-alpha and IFN-gamma decreased fatty acid synthesis, only TNF significantly decreased the mRNA levels of both acetyl CoA carboxylase and fatty acid synthase, the key enzymes in fatty acid synthesis. IFN-alpha and IFN-gamma decreased fatty acid synthase mRNA levels without significantly altering acetyl CoA carboxylase mRNA. IL-1 caused a slight increase in fatty acid synthesis and increased acetyl CoA carboxylase mRNA levels. Finally, while all cytokines increased lipolysis, hormone sensitive lipase mRNA levels were decreased by TNF, IFN-alpha and IFN-gamma treatment. These results indicate that the regulation of adipocyte lipid metabolism by cytokines is complex and that coordinate changes in mRNA levels cannot account for the observed metabolic changes.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗

PubMed1994

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

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

3T3 Cells↗

PubMed1993

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

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

Acquired Immunodeficiency Syndrome↗

PubMed1993

The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B.

Plasma low density lipoproteins (LDL) comprise multiple discrete subclasses, differing in size, density, and chemical composition. Gradient gel electrophoresis of LDL has demonstrated three common subclass patterns based on the predominant LDL subclass: large LDL, designated subclass pattern A; small LDL particles, designated subclass pattern B; and an intermediate pattern. Genetic studies have demonstrated that these patterns are inherited, but several lines of evidence suggest that environmental factors are important in the phenotypic expression of the pattern. The LDL B pattern is associated with increased levels of plasma triglyceride, reduced high density lipoprotein (HDL), and obesity. To better define the role of environmental factors on LDL phenotypic expression, we determined LDL patterns in patients with the acquired immunodeficiency syndrome (AIDS), an infection characterized by hypertriglyceridemia and weight loss. Similar to previous studies, plasma triglyceride levels were increased, whereas plasma cholesterol, LDL cholesterol, and HDL cholesterol levels were decreased in the AIDS subjects compared to those in age-matched controls. The percentage of AIDS subjects with the LDL B phenotype was increased 2.5-fold, demonstrating an increased prevalence of the LDL B phenotype in an acquired form of hypertriglyceridemia. For each LDL phenotype in AIDS, serum triglyceride levels were higher than the same phenotypic pattern in controls, with the most marked elevations in triglycerides found in AIDS subjects with the LDL B phenotype. In contrast to what was observed in controls, HDL cholesterol levels were decreased in all AIDS subjects and were unrelated to LDL pattern. Total and LDL cholesterol levels were higher in controls with the LDL B phenotype than in those with the LDL A phenotype, but there was no difference in total and LDL cholesterol in AIDS subjects with LDL B compared to A. On multiple regression analysis in subjects with AIDS, plasma triglyceride levels, age, and HDL cholesterol all contribute to the occurrence of the LDL B phenotype, but elevations in plasma triglyceride levels are the strongest independent predictor. Body mass index was not a predictor of LDL B phenotype in AIDS. These results suggest that disturbances in triglyceride metabolism that are caused by AIDS lead to the appearance of the LDL subclass B phenotype and provide further evidence that environmental or disease states that perturb lipid metabolism can produce an increased prevalence of the LDL B phenotype.

Acquired Immunodeficiency Syndrome↗

PubMed1992

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↗

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

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↗

PubMed1992

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↗

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

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↗

PubMed1991

Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome.

PURPOSE: The metabolic disturbances seen during infection are thought to be due to cytokines, modulators of the immune response. The acquired immunodeficiency syndrome (AIDS) is characterized by a high prevalence of hypertriglyceridemia and at times depletion of body cell mass (wasting). Elevated circulating levels of cytokines have also been reported in AIDS. Therefore, we determined the relationship between circulating cytokine levels and lipid levels and between circulating cytokine levels and wasting in AIDS and human immunodeficiency virus (HIV) infection. PATIENTS AND METHODS: Serum samples from 45 patients with AIDS, 13 subjects with evidence of HIV infection by presence of antibody but without AIDS (HIV positive), and 17 seronegative control subjects who had previously undergone body composition analysis were analyzed for triglyceride, cholesterol, interferon, tumor necrosis factor (TNF), and interleukin-1 levels. Eleven subjects with AIDS or HIV infection had sequential measurements. Interferon was analyzed by bioassay with identification using specific antibodies. TNF and interleukin-1 were assayed by enzyme-linked immunosorbent assay. Lean body mass was assessed by total body potassium. RESULTS: Serum interferon-alpha levels were significantly elevated in patients with AIDS (p less than 0.001 compared to controls), with detectable levels in 84% of AIDS patients. Interferon-alpha was not detectable in serum from controls, while three of 13 HIV-positive subjects had detectable interferon-alpha levels. There was a significant correlation between interferon-alpha levels and serum triglyceride levels in AIDS and HIV-positive patients (R = 0.446, p less than 0.002). There was no relationship between interferon-alpha and serum cholesterol levels (R = -0.039, NS). In contrast only 11% of AIDS patients had detectable circulating TNF levels; the mean value for and the prevalence of detectable serum TNF levels were not significantly different from those of control subjects. Interleukin-1 was not detected in the circulation. There was no correlation between the presence of circulating TNF and serum triglycerides. There was no relationship between circulating interferon-alpha or TNF levels and the presence of wasting as measured by total body potassium. CONCLUSION: These studies suggest that interferon-alpha, which has previously been shown to modulate lipid metabolism in vivo and in vitro, may be responsible for the hypertriglyceridemia found in AIDS.

Acquired Immunodeficiency Syndrome↗

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

Tumor necrosis factor-increased hepatic very-low-density lipoprotein production and increased serum triglyceride levels in diabetic rats.

Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (approximately 2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 micrograms TNF/200 g body wt, and the half-maximal effect is observed with 5 micrograms TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t 1/2; diabetic vs. TNF-administered diabetic, 3.5 +/- 0.7 vs. 4.0 +/- 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

PubMedDate not supplied

Effect of interleukin-1 on lipid metabolism in the rat. Similarities to and differences from tumor necrosis factor.

Infection and inflammation are associated with hypertriglyceridemia, which is thought to be mediated by cytokines. Previous studies at our laboratory and others have shown that tumor necrosis factor acutely increases serum triglyceride levels primarily by stimulating hepatic lipid synthesis and secretion. The role of interleukin-1 (IL-1), a cytokine that is also secreted by stimulated macrophages and that has many actions that overlap those of tumor necrosis factor, has not been studied in depth. The present study demonstrates that IL-1, at doses similar to those that cause fever and anorexia and that stimulate adrenocorticotropic hormone secretion, rapidly increases serum triglyceride levels; this elevation persists for at least 17 hours. Serum cholesterol levels are not altered by IL-1. Neither is the clearance of triglyceride-rich lipoproteins affected by IL-1. However, hepatic triglyceride secretion, measured by the Triton WR-1339 technique, is increased in IL-1-treated animals. Accompanying this stimulation in hepatic lipid secretion is an increase in de novo fatty acid synthesis in the liver. IL-1 does not increase serum free fatty acid and glycerol levels, suggesting that IL-1 does not stimulate lipolysis in vivo. Additionally, inhibition of lipolysis does not prevent the increase in serum triglyceride levels, providing further evidence that lipolysis does not play a crucial role in the increased hepatic lipid synthesis and secretion induced by IL-1. In contrast, tumor necrosis factor increases lipolysis, which contributes to the increase in serum triglycerides. That multiple cytokines rapidly elevate plasma triglyceride levels suggest that these changes in lipid metabolism may play an important role in the organism's response to infection and inflammation.

Animals↗