Biomedical subjects

A H Moser

Publications and source records attributed to A H Moser.

At least 37 records · Page 2Linked to original sources

PubMed1997

LPS and cytokines regulate extra hepatic mRNA levels of apolipoproteins during the acute phase response in Syrian hamsters.

Altered hepatic expression of apolipoproteins occurs during the acute phase response. Here we examined whether the acute phase response alters extra hepatic expression of apolipoproteins. Syrian hamsters were injected with endotoxin (LPS), tumor necrosis factor (TNF), interleukin (IL)-1, or the combination of TNF + IL-1 and mRNAs for serum amyloid A (apoSAA), apolipoprotein (apo) J, apo E. apo A-I, and apo D, were analyzed. LPS increased mRNA levels for apoSAA in all tissues examined. LPS and TNF + IL-1 increased mRNA levels for apo J in kidney, heart, stomach, intestine, and muscle. Individually, TNF and IL-1 were less potent than the combination of the two cytokines. LPS decreased mRNA levels for apo E in all tissues, except for mid and distal intestine. TNF and IL-1 were less effective than LPS. LPS, TNF + IL-1 and TNF decreased mRNA levels for apo A-I in duodenum. mRNA for apo D decreased in heart, were unchanged in brain and increased in muscle, following LPS. The widespread extra hepatic regulation of the apolipoproteins during the acute phase response may be important for the alterations in lipid metabolism that occur during infection and inflammation as well as the immune response.

Acute-Phase Reaction↗

PubMed1997

Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response.

Previously, we reported that PTH-related protein (PTHrP) gene expression is induced in vital organs, including the liver, during endotoxemia. The liver plays a central role in the acute phase response (APR), a cytokine-mediated host defense against infection and inflammation that includes increased production of acute phase proteins and lipids by hepatocytes. Because PTHrP is thought to act locally at its site of production, in vivo studies were carried out to determine whether PTHrP could contribute to the induction of the hepatic APR. Hepatic PTHrP messenger RNA (mRNA) levels were induced acutely in rat liver in response to a near lethal dose of endotoxin. PTHrP protein, which was located by immunohistochemical staining in hepatocytes from both control and LPS-treated rats, was markedly induced in periportal hepatocytes in response to LPS treatment. Co-incident with this transient increase in PTHrP gene expression, PTH/PTHrP receptor mRNA levels were down-regulated. Administration of PTHrP(1-34), a PTH/PTHrP receptor agonist, to mice increased hepatic serum amyloid A (SAA) mRNA levels as well as circulating levels of SAA. In addition, PTHrP(1-34) increased serum triglyceride (TG) levels in rats and mice in a dose-dependent fashion. The hypertriglyceridemic effect of PTHrP(1-34) was accompanied by an increase in hepatic fatty acid synthesis. In contrast, PTHrP(7-34) amide, a receptor antagonist, had no effect on serum SAA or TG levels. These results, which provide evidence for the regulated expression of PTHrP in adult liver, suggest that PTHrP may be one additional member of the cytokine cascade produced locally in liver that can act to stimulate the hepatic acute phase response.

Acute-Phase Reaction↗

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

Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters.

Endotoxin alters the metabolism of lipoproteins, including that of high density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) facilitates exchange of HDL cholesterol for very low density lipoprotein (VLDL) triglyceride, leading to catabolism of HDL. We investigated the effects of endotoxin and cytokines on CETP in Syrian hamsters. Endotoxin induced a rapid and progressive decrease in serum CETP levels, by 48 h CETP had decreased to < 20% of control levels. Endotoxin also decreased CETP mRNA and protein levels in adipose tissue, heart, and muscle, the tissues with highest levels of CETP mRNA, providing a plausible mechanism for the endotoxin-induced decrease in circulating CETP. Dexamethasone did not mimic the effects of endotoxin on CETP, but the combination of tumor necrosis factor and interleukin-1 did, indicating that these cytokines may in part mediate the effects of endotoxin on CETP. The endotoxin-induced decrease in CETP may help maintain HDL cholesterol levels during infection and inflammation when increased triglyceride levels could drive the exchange of HDL cholesteryl ester for VLDL triglyceride. Maintaining circulating HDL may be important because HDL protects against the toxic effects of endotoxin and provides cholesterol for peripheral cells involved in the immune response and tissue repair.

Adipose Tissue↗

PubMed1996

Beta-nerve growth factor as a mediator of the acute phase response in vivo.

Nerve growth factor (NGF) is increased during inflammation and stress. Stress-induced increases in specific serum proteins, such as serum amyloid A (SAA) and serum triglyceride (TG) levels, are part of the acute phase response which is mediated by cytokines. We now report the effect of systemic administration of beta-NGF on levels of serum lipids and SAA. Beta-NGF induced a rapid and sustained increase in serum TG and free fatty acid (FFA) in a dose dependent manner, while decreasing serum cholesterol levels in rats. Additionally, beta-NGF increased hepatic mRNA levels and serum concentrations of SAA at 16 hours in mice. Thus, beta-NGF joins the list of cytokines and growth factors that can mediate the acute phase response.

Animals↗

PubMed1996

LIF and CNTF, which share the gp130 transduction system, stimulate hepatic lipid metabolism in rats.

We determined the effects of leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) on lipid metabolism in intact rats. Administration of LIF and CNTF increased serum triglycerides in a dose-dependent manner with peak values at 2 h. The effects of LIF and CNTF on serum cholesterol were very small, and serum glucose was unaffected. Both LIF and CNTF stimulated hepatic triglyceride secretion, hepatic de novo fatty acid synthesis, and lipolysis. Pretreatment with phenylisopropyl adenosine, which inhibits lipolysis, partially inhibited LIF- and CNTF-induced hypertriglyceridemia. Interleukin-4, which inhibits cytokine-induced hepatic fatty acid synthesis, also partially inhibited LIF- and CNTF-induced hypertriglyceridemia. These results indicate that both lipolysis and de novo fatty acid synthesis play a role in providing fatty acids for the increase in hepatic triglyceride secretion. Neither indomethacin nor adrenergic receptor antagonists affected the hypertriglyceridemia. The combination of LIF plus CNTF showed no additive effects consistent with the action of both cytokines through the gp130 transduction system. Thus LIF and CNTF have similar effects on lipid metabolism; they join a growing list of cytokines that stimulate hepatic triglyceride secretion and may mediate the changes in lipid metabolism that accompany the acute phase response.

Animals↗

PubMed1996

Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to endotoxin-induced mortality in rodents.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is a ubiquitous and highly conserved vasoactive peptide whose role and regulation in normal physiology remain an enigma. Recently, we demonstrated that low-dose endotoxin (LPS) induces intrasplenic, but not systemic, levels of PTHrP; and that tumor necrosis factor, a pro-inflammatory cytokine, is the major mediator of this effect. We have therefore hypothesized that, with higher, lethal doses of endotoxin, PTHrP could be induced in multiple tissues to such a degree that it could contribute to the lethality of septic shock. MATERIALS AND METHODS: Northern blot analysis was used to measure PTHrP mRNA levels in vital organs of rats after administration of a near lethal dose (5 mg/250 g) of LPS (or vehicle alone). Plasma levels of PTHrP were also measured by immunoradiometric assay. The ability of the immunoglobulin fraction of two different PTHrP(1-34) antisera to protect from LPS-induced lethality was also studied in mice using survival analysis. RESULTS: In response to a near-lethal dose of endotoxin, PTHrP mRNA levels increased acutely in every vital organ examined (spleen, lung, heart, kidney, and liver). Circulating levels of PTHrP also increased, peaking 2 hr after administration of high-dose endotoxin. Passive immunization of mice with anti-PTHrP(1-34) antibody 6 hr prior to administration of a lethal dose of LPS protected mice from endotoxin-induced death (p < 0.00005). CONCLUSIONS: These results suggest that PTHrP belongs to the cascade of pro-inflammatory cytokines induced during lethal endotoxemia that is responsible for the toxic effects of LPS.

Animals↗

PubMed1996

Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity.

Endotoxin (LPS) and cytokines increase cholesterol synthesis and the secretion of lipoproteins by the liver in rodents resulting in hypercholesterolemia. Cholesterol 7 alpha-hydroxylase (CAH) is the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, the major regulated pathway by which cholesterol is eliminated from the body. Decreases in CAH would increase the quantity of cholesterol available for lipoprotein production. In the present study, we demonstrate that LPS, TNF, or IL-1 administration to Syrian hamsters produces a marked decrease in the levels of CAH mRNA in the liver. This marked decrease occurred even when the basal level of CAH expression was increased by feeding the bile acid sequestrant, colestipol. Additionally, a marked decrease was also observed when the animals were fed a cholesterol-enriched diet. Moreover, the decrease in CAH mRNA occurred very rapidly (decreased 66% by 90 min after LPS administration) and required relatively small doses of LPS (100 ng/100 g body weight). Lastly, the decrease in mRNA levels was accompanied by a decrease in CAH activity. This decrease in CAH could contribute to the increase in hepatic lipoprotein production induced by LPS and cytokines. CAH can be added to the growing list of proteins that regulate lipid metabolism and that are altered during the acute phase response.

Animals↗

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

Keratinocyte growth factor increases fatty acid mobilization and hepatic triglyceride secretion in rats.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that was originally identified as a keratinocyte mitogen after isolation from a lung fibroblast cell line. In this study, we demonstrate that administration of KGF to mice and rats elevates serum lipid levels. In rats, 1 h after KGF administration, serum triglyceride and FFA levels were increased, with peak values at 2 h (1.9-fold increase). The increase in serum triglyceride levels was sustained for at least 16 h. Serum cholesterol levels were also increased, but the effect was delayed beginning at 4 h, with peak values at 16 h (1.27-fold increase). KGF did not decrease the clearance of triglyceride-rich lipoproteins, but increased hepatic triglyceride secretion. KGF stimulated lipolysis, but not hepatic de novo fatty acid synthesis, and the increased delivery of FFA to the liver plays a crucial role in the KGF-induced hypertriglyceridemia. Neither alpha- nor beta-adrenergic receptor antagonists affected the hypertriglyceridemia induced by KGF, indicating that endogenous catecholamines are not involved in mediating KGF-induced hypertriglyceridemia. These results demonstrate that KGF induces hypertriglyceridemia by increasing hepatic triglyceride secretion, with the fatty acids provided by lipolysis making a major contribution. Thus, KGF could modulate lipid metabolism in vivo.

Animals↗

PubMed1995

Interleukin-6 stimulates hepatic triglyceride secretion in rats.

Interleukin-6 (IL-6) not only regulates a variety of immune functions, but also is the most potent cytokine in inducing the hepatic acute phase proteins. We determined the effect of IL-6 on serum lipid levels and the mechanism of IL-6-induced hypertriglyceridemia in rats. Intravenous administration of IL-6 (0.1-10 micrograms/200 g BW) increased serum triglyceride levels in a dose-dependent manner. One hour after IL-6 administration, serum triglyceride levels were increased, with peak values at 2 h (2.2-fold increase). Serum cholesterol levels also increased, but the effect was delayed, first occurring at 4 h and peaking at 8 h (1.24-fold increase). IL-6 treatment increased hepatic triglyceride secretion without decreasing the clearance of triglyceride-rich lipoproteins, indicating that the hypertriglyceridemia was due to increased secretion by the liver. Furthermore, IL-6 stimulates lipolysis, and the increased delivery of FFA to the liver significantly contributed to the IL-6-induced hypertriglyceridemia. Neither alpha 1- nor beta-adrenergic receptor antagonists affected the hypertriglyceridemia induced by IL-6, whereas previous studies have shown that endotoxin-induced hypertriglyceridemia was blocked by alpha-adrenergic receptor antagonists. These results demonstrate that IL-6 induces hypertriglyceridemia by stimulating hepatic triglyceride secretion independent of endogenous catecholamines. Thus, changes in hepatic triglyceride metabolism are another acute phase response that can be induced by IL-6.

Animals↗

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↗

PubMed1995

Lipoteichoic acid stimulates lipolysis and hepatic triglyceride secretion in rats in vivo.

The host response to infection is frequently accompanied by changes in lipid metabolism. Previous studies have shown that endotoxin (LPS), a component of the cell wall of gram-negative bacteria, increases serum lipid levels. In this study, we demonstrate that lipoteichoic acid (LTA), a component of the cell membrane of gram-positive bacteria, also increases serum lipid levels in rats in a dose-dependent manner (0.1-300 micrograms/200 g body weight). Serum triglyceride levels increased within 2 h after LTA administration with peak values at 4 h (2-fold increase). Serum cholesterol levels also increased but the effect was delayed occurring at 16 h and was relatively small (1.2-fold increase). LTA (10 micrograms/200 g BW) did not decrease adipose tissue lipoprotein lipase activity or the clearance of triglyceride-rich lipoproteins. Rather, the LTA-induced hypertriglyceridemia is due to an increase in hepatic triglyceride secretion. LTA stimulates both hepatic de novo fatty acid synthesis and lipolysis. The increased delivery of free fatty acids to the liver plays a major role in the LTA-induced hypertriglyceridemia. Pretreatment with phentolamine, an alpha-adrenergic receptor antagonist, and alprenolol, a beta-adrenergic receptor antagonist, or phentolamine alone significantly suppressed the hypertriglyceridemia induced by LTA. These adrenergic inhibitors had no significant effect on the increase in lipolysis. These results indicate that catecholamines are involved in mediating the LTA-induced increase in hepatic triglyceride secretion via alpha-adrenergic receptors. These changes in lipid metabolism may play an important role in the organism's response to gram-positive infection.

Adipose Tissue↗

PubMed1994

Diabetes increases hepatic hydroxymethyl glutaryl coenzyme A reductase protein and mRNA levels in the small intestine.

Previous studies have shown that both cholesterol synthesis and the activity of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, are increased in the small intestine of a wide variety of different animal models of diabetes. In the present study, we demonstrate that the mass of HMG CoA reductase protein is increased in the small intestine of both streptozocin-induced diabetic rats (2.5-fold) and streptozocin/alloxan-induced diabetic dogs (2.4-fold). These increases in HMG CoA reductase protein mass are of a magnitude similar to the previously observed increases in either HMG CoA reductase activity and/or cholesterol synthesis in the small intestine of diabetic animals. Furthermore, mRNA levels for HMG CoA reductase in the small intestine of diabetic rats and diabetic dogs are increased 2.1- and 1.7-fold, respectively. These results suggest that the increase in HMG CoA reductase protein levels in the small intestine of diabetic animals is due to an increase in mRNA levels. In contrast, mRNA levels for HMG CoA reductase in the liver of diabetic rats are not increased. Additionally, mRNA levels for the low-density lipoprotein (LDL) receptor are also increased in the small intestine of diabetic animals (rats, 43%; dogs, 59%). The increase in small-intestinal cholesterol synthesis has the potential for adversely affecting lipoprotein metabolism and increasing the risk of atherosclerosis in diabetes.

Animals↗

PubMed1994

Fatty acid synthesis in obese insulin resistant diabetic mice.

Diabetes is associated with hypertriglyceridemia and it has been suggested that the intestine contributes to this elevation. Recent studies have shown that in animals with IDDM, fatty acid (FA) synthesis is decreased in the liver and increased in the small intestine (SI). The purpose of the present study was to measure FA synthesis in the liver and SI of animals with NIDDM. In both db/db and ob/ob animals the incorporation of 3H2O into FA was increased in the SI (10 fold in db/db and 2.2 fold in ob/ob). FA synthesis was also increased in the liver of NIDDM (9 fold in db/db and 6 fold in ob/ob). These results provide further evidence that diabetes leads to changes in lipid metabolism in the SI.

Animals↗

PubMed1994

Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.

Endotoxin (lipopolysaccharide [LPS]) stimulates the production of cytokines, which mediate many of the metabolic effects associated with infection. In LPS-sensitive C57B1/6 mice, LPS doses as low as 0.01 micrograms per mouse decreased adipose tissue lipoprotein lipase (LPL) activity by greater than 50%. In LPS-resistant C3H/HeJ mice, which do not produce cytokines in response to LPS, doses of LPS as high as 10 micrograms per mouse did not affect LPL activity in adipose tissue. In muscle of C57Bl/6 mice, LPL activity was decreased by 27% after 10 micrograms of LPS, whereas in C3H/HeJ mice there was no effect. These results indicate that the LPS-induced decrease in both adipose and muscle LPL activity is mediated by cytokines. Tumor necrosis factor (TNF), interleukin (IL)-1, leukemia-inhibiting factor (LIF), interferon alfa, and interferon gamma all decreased adipose tissue LPL activity in intact mice. In skeletal and cardiac muscle, only IL-1 and interferon gamma decreased LPL activity, whereas TNF, LIF, and interferon alfa had no effect. Inhibition of TNF activity blocked the increase in serum triglycerides that is characteristically observed after LPS but did not affect the ability of LPS to decrease adipose tissue LPL activity. Inhibition of IL-1 activity with IL-1 receptor antagonist partially inhibited the increase in serum triglycerides; however, the ability of LPS to decrease LPL activity in either adipose or muscle tissue was not affected. These data indicate that although TNF and IL-1 play a role in mediating the increase in serum triglyceride levels, these cytokines do not play a crucial role in the inhibition of either adipose or muscle LPL activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗