Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome.

BACKGROUND: Hypertriglyceridemia is a result of reduced triglyceride (TG)-rich lipoprotein (TRL) catabolism and occurs in rats with nephrotic syndrome (NS) and in Nagase analbuminemic rats (NARs). While the heparin-releasable lipoprotein lipase (LpL) pool in NAR and in NS is similar, TG levels are significantly greater in NS, suggesting that factors other than reduced LpL alone act in NS but not in NARs. Furthermore, clearance of chylomicrons (CM) and very low-density lipoprotein (VLDL) is normal in vivo in NAR despite low LpL levels. We tested the hypotheses that impaired binding of VLDL and impaired VLDL-high density lipoprotein (HDL) interactions contribute to hyperlipidemia in NS. METHODS: TG and apoB secretion was measured using Triton WR 1339. Clearance of CMs by perfused hearts from NS and NAR was determined. Binding of VLDL from control, NS and NAR to rat aortic endothelial cells (RAECs) was measured prior to and following incubation with HDL from NS, NARs, and control. ApoE, protein, and TG content was determined. RESULTS: TG levels were greatest in NS (516 +/- 95 mg/dL), intermediate in NAR (193 +/- 20), and least in control (97 +/- 16, P = 0.05), while in contrast, TG secretion was least in NS (178 +/- 33 mg/dL/hour) versus 212 +/- 17 in NAR and 294 +/- 15 in control (P < 0.001 vs. NS). Clearance of CMs by NS and NAR hearts was the same and significantly reduced versus control (P < 0.005). Binding of NS-VLDL to endothelial cells was reduced, while NAR-VLDL binding was increased versus control (P < 0.001). Incubation of NS-VLDL with control or NAR HDL increased VLDL binding compared with binding following incubation with NS HDL (P < 0.001). CONCLUSION: Increased TG levels in both NS and NAR are the result of decreased TRL clearance. TG levels are greater in NS because of the presence of a combined defect: (1) a decrease in endothelial-bound LpL that occurs as a consequence of reduced serum albumin concentration, and (2) a defect in VLDL binding to endothelial-bound LpL. This latter defect occurs only in the presence of proteinuria and is conferred by HDL.

Infection and inflammation induce LDL oxidation in vivo.

Epidemiological studies have shown an increased incidence of coronary artery disease in patients with chronic infections and inflammatory disorders. Because oxidative modification of lipoproteins plays a major role in atherosclerosis, the present study was designed to test the hypothesis that the host response to infection and inflammation induces lipoprotein oxidation in vivo. Lipoprotein oxidation was measured in 3 distinct models of infection and inflammation. Syrian hamsters were injected with bacterial lipopolysaccharide (LPS), zymosan, or turpentine to mimic acute infection, acute systemic inflammation, and acute localized inflammation, respectively. Levels of oxidized fatty acids in serum and lipoprotein fractions were measured by determining levels of conjugated dienes, thiobarbituric acid-reactive substances, and lipid hydroperoxides. Our results demonstrate a significant increase in conjugated dienes and thiobarbituric acid-reactive substances in serum in all 3 models. Moreover, LPS and zymosan produced a 4-fold to 6-fold increase in conjugated diene and lipid hydroperoxide levels in LDL fraction. LPS also produced a 17-fold increase in LDL content of lysophosphatidylcholine that is formed during the oxidative modification of LDL. Finally, LDL isolated from animals treated with LPS was significantly more susceptible to ex vivo oxidation with copper than LDL isolated from saline-treated animals, and a 3-fold decrease occurred in the lag phase of oxidation. These results demonstrate that the host response to infection and inflammation increases oxidized lipids in serum and induces LDL oxidation in vivo. Increased LDL oxidation during infection and inflammation may promote atherogenesis and could be a mechanism for increased incidence of coronary artery disease in patients with chronic infections and inflammatory disorders.

Oxidized cholesterol in the diet accelerates the development of atherosclerosis in LDL receptor- and apolipoprotein E-deficient mice.

The aim of the current study was to determine whether oxidized cholesterol in the diet accelerates atherosclerosis in low density lipoprotein receptor- (LDLR) and apolipoprotein E- (apo E) deficient mice. Mice were fed either a control diet or a diet containing oxidized cholesterol. For LDLR-deficient mice, the control diet consisted of regular mouse chow to which 1.0% cholesterol was added. The oxidized diet was identical to the control diet except that 5% of the added cholesterol was oxidized. In apo E-deficient mice, the control diet contained 0.15% cholesterol, whereas in the oxidized diet, 5% of the added cholesterol was oxidized. LDLR-deficient and apo E-deficient mice were fed the experimental diets for 7 and 4 months, respectively. In mice fed the oxidized-cholesterol diets, the levels of oxidized cholesterol in sera were increased. At the end of the experiment, aortas were removed and atherosclerosis was assessed. We found that in LDLR-deficient mice, feeding of an oxidized-cholesterol diet resulted in a 32% increase in fatty streak lesions (15.93+/-1.59% versus 21.00+/-1.38%, P<0.03). Similarly, in apo E-deficient mice, feeding of an oxidized-cholesterol diet increased fatty streak lesions by 38% (15.01+/-0.92% versus 20. 70+/-0.86%, P<0.001). The results of the current study thus demonstrate that oxidized cholesterol in the diet accelerates fatty streak lesion formation in both LDLR- and apo E-deficient mice.

Effect of oxidized lipids in the diet on oxidized lipid levels in postprandial serum chylomicrons of diabetic patients.

OBJECTIVE: To determine whether humans with type 2 diabetes have increased levels of oxidized fatty acids in their serum chylomicron fraction after the ingestion of dietary oxidized fatty acids. RESEARCH DESIGN AND METHODS: The study was performed on 31 male type 2 diabetic patients and 24 age-matched control subjects. Among the diabetic patients, 22 had poor glycemic control, defined as HbA1 > 10% (normal value < 7.7%). Nine patients had good glycemic control (HbA1 < or = 10). Heated corn oil containing low or high levels of oxidized fatty acids was used as a test meal. At 2.5 h after the test meal, 50-ml blood samples were obtained from all subjects, and the chylomicron fraction (Sf > 1,000) was isolated. The degree of oxidation in chylomicrons was determined by measuring conjugated dienes. For determining the postprandial levels of triglycerides and of oxidized lipids in serum chylomicrons over an extended time period, blood samples were obtained at 0, 2.5, 5.0, and 7.5 h for isolation of chylomicrons and determination of fatty acid oxidation. RESULTS: We found that at 2.5 h after the consumption of the test meal containing either a low or high oxidized fatty acid content, conjugated dienes in serum chylomicrons in diabetic subjects in poor glycemic control were increased compared with those in control subjects. Diabetic patients in good glycemic control had similar levels of oxidized lipid in their chylomicrons when compared with control subjects. Additionally, in diabetic patients in poor glycemic control, the levels of oxidized lipids in chylomicrons remained elevated for an extended post-prandial period. CONCLUSIONS: In diabetic subjects with poor glycemic control, dietary oxidized lipids induce an exaggerated and sustained increase in the levels of oxidized lipids in chylomicrons when compared with either control subjects or diabetic patients with good glycemic control. These increased postprandial levels of potentially atherogenic oxidized lipids may contribute to the accelerated atherosclerosis associated with diabetes.

Structural characterization and functional effects of a circulating heparan sulfate in a patient with hepatocellular carcinoma.

A circulating anticoagulant was isolated from the plasma of a 42-year-old man with cirrhosis and hepatocellular carcinoma who had an unusual coagulation test profile. The patient developed a fatal coagulopathy, unresponsive to protamine therapy or plasma exchange following liver biopsy. However, at presentation, routine hemostasis assays were normal. The patient had mucocutaneous bleeding but the sole laboratory abnormality was a prolonged thrombin time (TT = 99 s, normal 25-35 s). Protamine titration indicated activity equivalent to a heparin concentration of 6-7 U/ml. Antithrombin III (AT III) antigen and activity were markedly elevated. The anticoagulant activity, purified from plasma by DEAE chromatography, was identified as a glycosaminoglycan (GAG). GAG anti-thrombin activity was completely abolished by heparin lyase III. Based on the degree of sulfation and HPLC pattern, the GAG was classified as heparan sulfate. Low levels (4 microM) of purified GAG markedly prolonged the TT (>120 s) but not the activated partial thromboplastin time (PTT) (31.4 s). In a Factor Xa assay, the GAG exhibited a potency equivalent to 0.06 U of low molecular weight heparin per nmol of uronic acid. Patients with endogenous circulating glycosaminoglycans can present with unusual laboratory coagulation test profiles. These reflect complex dysfunction of hemostasis, leading to difficulty in providing diagnosis and effective care.

Oxidized cholesterol in the diet accelerates the development of aortic atherosclerosis in cholesterol-fed rabbits.

Oxidized lipoproteins may play a role in atherosclerosis. Recently, we have demonstrated that the levels of oxidized fatty acids in the circulation correlate directly with the quantity of oxidized fatty acids in the diet and that dietary oxidized fatty acids accelerate atherosclerosis in rabbits. The present study tests the hypothesis that oxidized cholesterol in the diet accelerates the development of atherosclerosis. Rabbits were fed a diet containing 0.33% nonoxidized cholesterol (control diet) or the same diet containing 0.33% cholesterol of which 5% was oxidized (oxidized diet). Serum cholesterol levels increased to a similar extent in both groups, with the majority of cholesterol in the beta-VLDL fraction. Moreover, in the serum beta-VLDL fraction and liver, there was a significant increase in the oxidized cholesterol levels. Most importantly, feeding a diet enriched in oxidized cholesterol resulted in a 100% increase in fatty streak lesions in the aorta. Western diets contain high concentrations of oxidized cholesterol products, and our results suggest that these foods may be a risk factor for atherosclerosis.

Exposure to cigarette smoke delays the plasma clearance of chylomicrons and chylomicron remnants in rats.

We investigated the effects of cigarette smoke exposure on the clearance of chylomicrons (CM) and CM remnants in rats after administration of a fat-containing meal. There was a decrease in clearance of both postprandial CM and exogenous radiolabeled CM in smoke-exposed animals. For exogenous CM, clearance (t1/2) increased significantly for both triglyceride and cholesterol labels and correlated with the delay in liver uptake. This decrease in lipid clearance could not be explained by decreased lipoprotein lipase (LPL) activity because smoke exposure resulted in a significant increase in LPL activity. When the hydrolysis of CM by endothelial LPL was tested in a heart perfusion system, there was no difference in CM hydrolysis between the two groups. Hepatic lipase activity was also unchanged in smoke-exposed animals. However, there was a significant delay in the CM remnant uptake into livers isolated from smoke-exposed rats. Thus the delay in CM clearance in smoke-exposed animals cannot be attributed to reduced lipase activities but results from impaired hepatic uptake of CM remnants.

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.

Oxidized lipids in the diet accelerate the development of fatty streaks in cholesterol-fed rabbits.

Studies have indicated that oxidized lipoproteins may play a role in atherosclerosis. We have recently demonstrated that the levels of oxidized lipoproteins in the circulation can be directly correlated to the quantity of oxidized lipids in the diet. The present study tested the hypothesis that dietary oxidized lipids accelerate the development of atherosclerosis. For 12 to 14 weeks, 36 male New Zealand White rabbits were fed a low-cholesterol (0.25%) diet containing either 5% unoxidized corn oil (control diet) or 5% oxidized corn oil (oxidized-lipid diet). Serum cholesterol levels increased to a similar extent in both groups, with the majority of the cholesterol in the beta-migrating very low density lipoprotein (beta-VLDL) fraction. Beta-VLDL from control animals contained 3.86+/- 0.57 versus 9.07 +/- 2.14 nmol conjugated dienes per micromol cholesterol (P<.05) in rabbits fed the oxidized-lipid diet. No difference in oxidized lipid levels was detected in LDL. Most important, feeding a diet rich in oxidized-lipid resulted in a 100% increase in fatty streak lesions in the aorta. Additionally, rabbits that were fed the oxidized-lipid++ diet had a >100% increase in total cholesterol in the pulmonary artery that was primarily due to an increase in cholesteryl ester. Oxidized lipids are frequently present in the typical US diet, and our results suggest that consumption of these foods may be an important risk factor for atherosclerosis.

Oxidized lipids in the diet are incorporated by the liver into very low density lipoprotein in rats.

Previous studies have shown that the quantity of oxidized lipids in the diet directly correlates with the level of oxidized chylomicrons in mesenteric lymph and the level of oxidized lipids in endogenous lipoproteins such as very low density lipoprotein (VLDL) and low density lipoprotein (LDL). The aim of the present study was to determine whether oxidized fatty acids in the diet are delivered via chylomicrons to the liver and whether these lipids are repackaged and secreted in VLDL. In these experiments, oxidized [14C]linoleic acid was utilized as a marker for oxidized dietary fats. When we determined the metabolism of nonoxidized and oxidized [14C]linoleic acid-labeled chylomicrons, we found that hepatic uptake was similar with 13.57 +/- 0.84% of nonoxidized and 13.40 +/- 0.96% of oxidized linoleic acid delivered to the liver 30 min after chylomicron administration. Additionally, uptake by the extrahepatic tissues was also similar. When the hepatic secretion of VLDL was determined in an in vitro perfusion system after the administration of nonoxidized and oxidized linoleic acid-labeled chylomicrons to intact animals, we found that oxidized linoleic acid was utilized for the formation and secretion of VLDL. After the administration of labeled nonoxidized and oxidized linoleic acid, 0.86 +/- 0.07% and 0.70 +/- 0.09% of the administered label was found in the liver perfusate at 2 h, respectively. The presence of oxidized linoleic acid in oxidized VLDL was confirmed by demonstrating the presence of hydroperoxide-derived hydroxy octadecanoic acid. Thus, our findings demonstrate that oxidized dietary lipids are delivered to the liver via chylomicrons where they are utilized for synthesis of endogenous lipoproteins such as VLDL.

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.

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.

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.

Oxidized lipids in the diet are a source of oxidized lipid in chylomicrons of human serum.

We examined whether oxidized lipids in the diet determine the levels of oxidized lipid in human postprandial serum chylomicrons. After we fed subjects control corn oil containing low quantities of oxidized lipid, the levels of conjugated dienes in the chylomicron fraction were low (9.67 +/- 0.92 nmol/mumol triglyceride), and no thiobarbituric acid-reactive substances (TBARS) could be detected. However, when subjects were fed a highly oxidized oil, the conjugated diene content in chylomicrons was increased 4.7-fold to 46 +/- 5.63 nmol/mumol triglyceride, with 0.140 +/- 0.03 nmol TBARS/mumol triglyceride. When subjects were fed medium-oxidized oil, the degree of oxidation of the chylomicron lipids was moderately increased (21.86 +/- 2.03 nmol conjugated dienes/mumol triglyceride). Additionally, we found that chylomicrons isolated after ingestion of oxidized oil were more susceptible to CuSO4 oxidation than chylomicrons isolated after ingestion of the control oil. The lag time for oxidation decreased from 4.30 +/- 0.40 to 3.24 +/- 0.51 hours (P < .05). These data demonstrate that in humans dietary oxidized lipids are absorbed by the small intestine, incorporated into chylomicrons, and appear in the bloodstream, where they contribute to the total body pool of oxidized lipid.

The effect of oxidized lipids in the diet on serum lipoprotein peroxides in control and diabetic rats.

The levels of oxidized serum lipoproteins are increased in humans and animals with diabetes. We have examined the contribution of dietary oxidized lipids on the levels of oxidized lipoproteins. In both control and streptozocin induced diabetic rats, the oxidized lipid content of mesenteric lymph chylomicrons (CM) increased when increasing quantities of oxidized lipids were administered intragastrically. However, at all levels of administered oxidized lipids, the quantity of oxidized lipids in CM was greater in the diabetic animals. These results indicate that oxidized lipids are absorbed and packaged into CM and suggest that there is increased absorption of oxidized lipids in diabetic animals. In nondiabetic rats fed a fat-free diet, the levels of oxidized lipids in their serum lipoproteins were very low. When oxidized lipids were added to the diet, the quantity of peroxides in serum lipoproteins increased about fivefold. In diabetic animals fed a fat-free diet, there were also very low levels of oxidized lipids in their serum lipoproteins, and there was no difference between control and diabetic rats. However, when diabetic animals were fed a diet containing oxidized lipids, the quantity of oxidized lipids in their serum lipoproteins increased 16-fold and were significantly greater than in controls. Thus, in both control and diabetic rats the quantity of oxidized lipids in the diet largely determines the levels of oxidized lipids in circulating lipoproteins. However, in diabetic animals the effect of diet is more pronounced. Together with the CM studies, these results demonstrate that dietary oxidized lipids make a major contribution to the levels of oxidized lipids in circulating lipoproteins and indicate that increased absorption of oxidized lipids in diabetic animals may play a role in the elevation of oxidized lipoproteins observed in this disorder.

Cigarette smoke alters chylomicron metabolism in rats.

PURPOSE: Cigarette smoking may exert its atherogenic effect by delaying the plasma clearance of dietary fat and cholesterol, allowing more time for their interaction with the artery wall. To study the effects of smoke on chylomicron metabolism in rats, we examined the metabolic effects of smoke on both whole animals and chylomicron particles in vitro. METHODS: Carbon 14- and hydrogen 3-labeled chylomicrons were injected intravenously into smoke-treated rats and control rats that were not exposed to smoke (sham smoked). Plasma clearance, hepatic uptake, and heart binding were measured. In a second set of experiments, chylomicron particles were exposed to cigarette smoke in vitro by either: (1) passing smoke through chylomicrons suspended in saline solution (SCM) or (2) passing smoke through saline solution alone, then mixing the saline solution with chylomicrons (CM + SS). Normal (non-smoke exposed) rats were infused with either SCM, CM + SS, or control chylomicrons (CCM). Plasma clearance, hepatic uptake, and heart binding were again measured. RESULTS: The initial plasma clearance time of labeled chylomicrons did not differ between smoke-treated and control animals. However, hepatic uptake of chylomicron cholesterol was slower in smoke-treated animals (46.1% +/- 0.9% of injected dose) than in controls (61.5% +/- 2.1%, p < 0.001). In contrast, more labeled chylomicrons remained in the heart of smoke-treated rats than controls (0.89% +/- 0.18% vs 0.45% +/- 0.05%, p < 0.05). Disappearance of 14C-labeled cholesterol from blood was delayed in rats injected with SCM (half-life = 9.0 +/- 0.4 minutes) and CM + SS (half-life = 8.0 +/- 0.4 minutes), compared with the time in rats injected with CCM (6.6 +/- 0.3 minutes, p < 0.05). Hepatic uptake of SCM (40.6% +/- 1.9% of injected dose) and CM + SS (45.0% +/- 1.9%) was less than that of CCM (60.7% +/- 4.4%, p < 0.05). In addition, the binding to the heart increased from 0.97% +/- 0.29% (CCM) to 2.45% +/- 0.30% with the infusion of SCM (p < 0.05). The binding in the heart of CM + SS (0.95% +/- 0.04%) was not different from that of CCM. CONCLUSIONS: These data demonstrate for the first time that cigarette smoke exposure prolongs chylomicron residence time in tissues (heart) and delays hepatic uptake of chylomicron cholesterol in rats. The effect is present when either the animal or the chylomicron particle is exposed to smoke. We hypothesize that prolonged binding of relatively cholesterol-rich chylomicron remnants to endothelial surfaces could create a more atherogenic postprandial milieu.

Defective lipolysis persists in hearts of rats with heymann nephritis in the absence of nephrotic plasma.

Catabolism of triglyceride-rich lipoproteins, including chylomicrons (CM), is reduced in the nephrotic syndrome. It has been suggested that hyperlipidemia per se might lead to reduced CM catabolism by saturating catabolic sites. Evidence also implicates disordered high-density lipoprotein function as reducing the activity of lipoprotein lipase (LPL), the final effector of CM lipolysis. To establish whether CM lipolysis would be abnormal in the absence of either abnormal rat lipoproteins or hyperlipidemia, we measured CM lipolysis by isolated perfused hearts of rats with passive Heymann nephritis. We found that lipolysis was significantly reduced by 30% at 30 minutes (246 +/- 40 mumol v 164 +/- 10 mumol fatty acid released/hr, P < 0.05). Uptake of fatty acids was also significantly less in nephrotic hearts than in control hearts (7.25% +/- 0.93% of dose v 3.32% +/- 0.011% of dose, P < 0.01). Total heart LPL activity was reduced by 40% in hearts of nephrotic animals (368.5 +/- 39.4 mumol v 210.6 +/- 25.9 mumol free fatty acid released/hr/g heart, P < 0.01). The heparin-releasable LPL pool is that pool bound to the vascular endothelium and represents the biologically active fraction. We perfused hearts with heparin and found that heparin-releasable LPL was reduced by an order of magnitude in hearts from nephrotic rats (173 +/- 33 mumol v 19.4 +/- 11.7 mumol free fatty acid released/hr/heart, P < 0.001). The decrease in this pool represented nearly entirely the difference in total heart LPL in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dietary lipid peroxides on metabolism of serum chylomicrons in rats.

We have found that in rats the peroxide content of chylomicrons (CM) is determined by the lipid peroxide concentration in the diet, indicating that dietary lipid peroxides are incorporated into the lymph CM. Moreover, these incorporated lipid peroxides influence the normal CM metabolism. When radiolabeled CM were injected into rats, there was no difference in the initial plasma removal between CM prepared from oil with low peroxide content (control CM) and CM prepared from oil with high peroxide content (oxidized CM). However, the tissue distribution of the labels indicated that the hepatic uptake of CM decreased with increasing lipid peroxide content of CM. At 10 min after injection of CM, liver uptake of cholesterol label was 48.39 +/- 3.08% for control CM and 31.41 +/- 10.73% for oxidized CM. Vitamin E enrichment of control CM increased their hepatic uptake to 61.07 +/- 0.83%. Additionally, binding of oxidized CM to the heart endothelium increased from 2.55 to 3.60% compared with binding of control CM. When the hydrolysis of control and oxidized CM by endothelial lipoprotein lipase (LPL) was tested in a heart perfusion system, we found that after 30 min, 56.51 +/- 5.81% of control and 76.82 +/- 1.75% of oxidized CM were not hydrolyzed and remained in the perfusate. Thus our results indicate that the altered metabolism of oxidized CM may be related to a reduced hydrolysis rate by endothelial LPL.

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.

Both peripheral chylomicron catabolism and hepatic uptake of remnants are defective in nephrosis.

We showed previously that proteinuria caused delayed chylomicron (CM) clearance in the rat and postulated the existence of a primary defect in CM hydrolysis. It was possible that reduced CM clearance resulted from increased lipogenesis causing saturation of catabolic sites and not from a primary defect in CM catabolism. To clarify this point we measured kinetically the absolute rate of triglyceride (TG) uptake from CM in rats with Heymann nephritis (HN) and normal Sprague-Dawley rats (SD) and determined TG uptake in individual tissues using [3H]TG- and [14C]cholesterol-labeled CM. Hepatic [14C]cholesterol uptake was reduced in HN (69.3 +/- 6 vs. 7.2 +/- 2% of dose, P less than 0.001). TG uptake was reduced in HN measured kinetically (1.01 +/- 0.09 vs. 0.213 +/- 0.028 mg TG.min-1.100 g body wt-1, P less than 0.001) and reduced in all tissues (heart, skeletal muscle, fat, and liver). CM are catabolized on the vascular endothelium to atherogenic, cholesterol-rich remnant (CM remnant) particles, which are then rapidly taken up by the liver. We measured hepatic CM remnant uptake in SD and in HN using [14C]cholesterol-labeled CM remnant. CM remnant uptake was significantly reduced in HN (58 +/- 1.2 vs. 20 +/- 0.86% uptake, P less than 0.01). CM remnants were increased significantly in plasma of HN. Thus the nephrotic syndrome causes a primary defect in the uptake of TG from CM that is expressed in all tissues and a separate defect in hepatic CM remnant uptake. Although CM remnant generation is impaired because of defective CM hydrolysis, the defect in hepatic CM remnant uptake is so severe that these particles accumulate in blood, posing a potential risk for atherogenesis.