The lipid pattern in HIV infection

Tuesday I I October 1994: Poster Abstracts Triglycerides

been suggested that the interaction of APA with a co-factor (apolipoprotein-H, a component of VLDL) is directly associated with thrombosis. TG could be related to this co-factor. Prospective studies am needed to confirm these preliminary conclusions and to know if dietary measures or drug therapy resulting in reduction in TG decreases the risk for thrombosis in these patients. 11361 m,

Differential utilization of cholesterol from chylomicrons derived from corn oil or palm oil for biliary steroid secretion in the rat in vivo Mayes PA, Ortu G, Cantafora A, Bravo E, Dept. of

Veterinary Basic Sciences, The Royal Veterinary College, Univ. of London, London NW1 OTU, UK

It has been known for some time that plasma cholesterol concentrations are raised by dietary saturated fat and lowered by dietary polyunsaturated fat, but the exact mechanism of these effects remains unclear. The secretion of biliary steroids by the liver is a major mute for the removal of cholesterol from the body, and this study was designed to compare the effects of polyunsaturated and saturated fat on the excretion of chylomicron cholesterol via this pathway. Chylomicrons labeled with [3H]cholesteml were collected from the thoracic duct of rats tube-fed corn oil (polyunsaturated fat) or palm oil (saturated fat), administered intrajugularly to rats previously prepared with a bile fistula and biliary drained for 20-22 h. The clearance of radioactivity from the blood, its uptake by the liver and appearance in the bile were measured in the following 180 min. Biliary secretion of radioactivity (determined at 30-min intervals) was significantly lower (appmx. 50%) in experiments with chylomicrons derived from palm oil as than from corn oil at all time points after 30 min. In contrast, the time course of disappearance of radioactivity from the blood and its uptake by the liver after 180 min were no different in the two experimental groups. These results indicate that the hepatic processing of cholesterol of dietary origin to biliary steroids is influenced by the degree of saturation of fat in chylomicrons and chylomicron remnants, and this is likely to contribute to the hypo- and hypercholesterolemic effects of dietary polyunsaturated and saturated fat. 11371 m,

Influence of fatty acid saturation on chylomicron remnant metabolism in the perfused liver Botham KM, Mayes PA, Dept. of Veterinary Basic

Sciences, The Royal Veterinary College, Univ. of London, London NW1 OTU, UK

The effects on plasma lipids of variations in saturation of the fatty acids in the diet have not been adequately explained. We have compared the uptake and metabolism of chylomicron remnants derived from corn oil (polyunsaturated), olive oil (monounsaturated), and palm oil (saturated) in the perfused rat liver. Chylomicrons (>lOO nm) labeled with [3H]cholesteml and [14C]oleate were isolated from the thoracic duct of rats fed one of each of the oils, and were used to prepare chylomicmn remnants in functionally hepatectomized rats. Remnants were isolated and added to detibrinated, dialysed whole rat blood which was perfused through livers from fed rats in situ. Similar amounts (26-30%) of the labeled cholesterol and triacylglyceml added were found in the liver after 4 h for all mmnants. The recovery of 3H in bile acid was significantly less with palm oil (0.22%) than with corn oil (0.55%) or olive oil (0.78%) remnants. The proportion of [3H]cholesteml recovered in the bile as unesterifled [3H]cholesteml was also 50% less with palm oil remnants. A greater percentage of [14C]triac lglyceml from the olive oil remnants (0.96%) was oxidized to l&O, in comparison to that from corn (0.32%) or palm oil (0.29%) remnants. Since the

127

production of VLDL triacylglyceml by the liver is inversely proportional to fatty acid oxidation, these results suggest that less VLDL is produced from olive oil than from corn or palm oil remnants. As LDL cholesterol is derived from VLDL, these results are consistent with both plasma ttiacylglycerol and LDL cholesterol lowering effects of olive oil. Taken together with the reduced excretion via the bile of cholesterol from palm oil remnants, the results probably reflect underlying mechanisms responsible for the hypo- and hyperlipidemic effects of dietary monounsaturated and saturated fatty acids. Remnant-like particle-s isolated by hnmonoaffinity chromatography stimulate secretion of PAL1 from human aortic endothelial cells ma, Ishikawa Ta, Nishiwaki Ma, Higashi Ka, Nakajima Kb, Nakamura Ha, ‘1st Dept. Int. Med., National Defense Medical 11381

College, 3-2 Namiki, Tokorozuwa, Saitama, Japan 359; bJapan Immunoresearch Lab. Co. Ltd., Takasaki-city, Japan

Monoclonsl antibody to apo B-100 (Jr-H), which can also tecognize apo B48 and the apo E-rich fraction of TG-rich lipoproteins, can bind to other B-lOO-containing particles. We isolated unbound VLDL fractions containing more apo E and apo B48 by using a mixture of monoclonal antibodies to apo A-l and JI-H in our immunoaffinity chromatography system. We named the fractions ‘remnant-like particles’ (RLP). Hemostatic factors, fibrinogen, factor VII activity and plasma concentration of plasminogen activator inhibitor-l (PAI-1) ate known to be related to plasma triglyceride level, and these factors may influence the risk of coronary heart disease. In this study, we examined the relation between RLP and PAI- clinically and the effect of RLP and bound VLDL fractions on PAI- secretion by endothelial cells in vitro. The plasma concentration of PAI- was significantly related to plasma concentration of VLDL-TG (P
As hypertriglyceridemia is associated with HIV infection this study evaluated total cholesterol, triglycerides (enzymatic colorimetry), HDL-cholesterol (enzymatic calorimetry after PEG precipitation), LDL-cholesterol (Friedewald formula), apo A-I, B and Lp(a) (nephelometry) in 82 former drug abusers infected by HIV (58 M, 24 F). Patients were separated on the basis of the CD4 cell count and clinical category (CDC Classification, 1993) into two groups: AIDS (n = 30, 26 receiving Zidovudine (AZT) and four receiving Dideoxynosine (DDI) therapy), and HIVpositive without AIDS (n = 52, 32 under AZT, 4 under DDI and 16 with no therapy). The lipid pattern was also evaluated in an HIV-negative control group of 30 former drug abusers. Significant inter-group differences emerged in triglycerides (AIDS 195.5 mg/dl vs controls 104 mg/dl, P < 0.02) in HDLcholesterol (AIDS 29.8 mg/dl vs controls 43.8 mg/dl, P < 0.0001 and vs HIV positive 42.2, P < 0.0002), and in ape A-I (AIDS 118.6 mg/dl vs controls 139.5 mg/dl, P < 0.02, and vs HIV positive 141.9 mg/dl, P < 0.002). Significant positive correlations

Atherosclerosis X, Montreal, October 1994

128

Tuesday I I October 1994: Poster Abstracts Triglycerides

emerged between CD4 and HDL cholesterol (r= 0.435, P < 0.0001). Lipid pattern modification, which is more marked as HIV infection progresses towards AIDS, could explain the accelerated atherosclerosis often observed in these patients. Triglyceride levels should be monitored particularly in patients taking DDI, who are at greater risk of pancreatitis. Treatment of primary mixed hyperlipidemia with etophylline clofibrate: effects on lipoprotein composition, lipoprotein-modifying enzymes and postprandial lipoprotein metabolism Wger, Lechleitner M, Pfeiffer KP, Ritsch A, Tr6binger G, Honferwieser T, Patsch JR, Dept. of Med., Univ. of Innsbruck, Am’chstrasse 3.5,.A-6020 Innsbr&k, Austria .

1

In 17 patients with primary mixed hyperlipidemia we determined lipoprotein levels and lipoprotein composition in fasting plasma, lipoprotein-modifying enzymes and postprandial lipoprotein metabolism after an oral fat-tolerance test supplemented with vitamin A before and 12 weeks after treatment with etophylline clofibrate. Fasting plasma cholesterol, triglycerides, and the levels of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) decreased significantly; high density lipoprotein (HDL) cholesterol and the level of the less dense subfraction of HDL, HDb increased significantly. After treatment, the triglyceride content of LDL and HDb was significantly decreased. Concentrations of triglycerides, chylomicrons and chylomicron remnants measured in postprandial plasma after ingestion of the fatty test meal supplemented with vitamin A decreased by 33% 30% and 6%. respectively (P < 0.005; Pi 0.01; P < 0.05). The activity of lipoprotein lipase and hepatic lipase in postheparin plasma increased by 51% and 45%. respectively (P-z 0.01; P< 0.05); cholesteryl ester transfer protein (CETP) in fasting plasma decreased significantly. CETP mass, as determined by immunoradiometric assay was directly related to the triglyceride content of LDL both before (r = +0.46; P < 0.05) and after (r = +0.49; P < 0.05) treatment. Decreased triglyceride-rich lipoproteins and, possibly, decreased cholesteryl ester transfer protein after fibrate treatment are supposed to reduce accelerated plasma core lipid transfer, thereby tending to (i) normalize compositional abnormalities in all lipoprotein classes and (ii) elevate pathologically depressed HDb levels. We conclude that hypolipidemic treatment with etophylline clofibrate favorably affects the cardiovascular risk factor profile in primary mixed hyperlipidemia. Hepatic lipid metabolism in experimental nephrosis: decreased fatty acid oxidation and increased phosphatidate phosphohydrolase activity might contribute to the hyperlipidemia of the nephrotic syndrome .. Al_Shurball, Asiedu D, Humble E, Rudling M, Berge RK, Berglund L, Dept. of Clinical Chemistry, Karolinska Inst., Hud-

1

contrast, there was no significant effect of nephrosis on acetylCoA carboxylase. Of the enzymes involved in triglyceride biosynthesis, only microsomal PAP activity increased (32%) in nephrotic rats; microsomal GPAT activity decreased. No effect on DGAT, mitochondrial GPAT or cytosolic PAP could be detected. The activity of HMG-CoA reductase was not significantly different between the two experimental groups. A slight increase in hepatic cholesterol levels was observed, but no change in LDL receptor binding could be detected. Hepatic phospholipid levels were slightly reduced in nephrotic rats. The activity of microsomal CTP-phosphocholine cytidyltransferase decreased (24%). We conclude that a decrease in mitochondrial fatty acid oxidation with subsequent increase in the availability of fatty acids for esterification might be an important mechanism underlying hypertriglyceridemia of nephrotic syndrome. Further, an increase in PAP activity along with a decrease in the activity of CTPphosphocholine cytidyltransferase might enhance triglyceride synthesis in the liver. 1

Hypertriglyceridemia in childhood and adolescence: clinical, biochemical and molecular study ca JC, Levy E, Lambert M, Dept. of Pediatrics,

HGpital Sainte-Justine; Univ. de Montrkal, 3175 chemin C6te Sainte-Catherine, Mont&al, QC, Canada H3T I C5

Triglyceride (TG) levels may be important determinants of coronary artery disease risk. The objectives of our study were to determine the frequency of hypertriglyceridemia (TG >95th percentile on two occasions) in French Canadian children referred to our lipid clinic, and to characterize their clinical and biochemical phenotype. In addition, we wished to test the prevalence of the heterozygote state for LPL deficiency in these children. Carrier state for LPL deficiency was found to be common in French Canadians (11139). We reviewed the charts of the 459 French Canadian patients who attended the clinic between 1987 and 1993. 54 (11.7%), aged 1.25-16 years, presented persistent baseline hypertriglyceridemia (without LDL cholesterol ~-95th percentile 3.2%; with LDL-cholesterol >95th 8.5%). Hyperlipidemia secondary to an underlying disorder (excluding obesity) or drug treatment was suspected in 11.3% of these hypertriglyceridemic children. A parental history of hyperlipidemia was present in 846, and a family history of premature atherosclerosis in 57%. Blood pressure readings >90th percentile were found in 4.5% and body mass index >90th percentile, in 48%. HDL cholesterol levels were significantly lower than controls (P = 0.0016). DNA samples from 44/54 subjects were available for mutational analysis at the LPL locus. We screened for 3 missense mutations (P207L, G188E, D250N) accounting for 97% of the mutant alleles in French Canadians. None was a carrier of either mutation. In conclusion, only’ 12% of children seen at our lipid clinic had hypertriglycexidemia; most had a parental history of hyperlipidemia and/or a family history of premature atherosclerosis; obesity was frequent; and heterozygosity for LPL deficiency was not responsible for the hypertriglyceridemia in these subjects.

dinge Univ. Hospital, 141 86 Huddinge, Sweden

Increased lipoprotein secretion is well documented in nephrotic syndrome. However, the basis for this perturbation is uncertain. We have examined the possibility that changes in fatty acid metabolism and/or key enzymes in triglyceride and cholesterol synthesis might contribute to the hyperlipidemia of the nephrotic syndrome. Nephrotic rats displayed severe hypcrlipidemia, with 20- and 6-fold increases in plasma levels of triglycerides and cholesterol respectively. Hepatic triglyceride content almost doubled, and hepatic VLDL-TG secretion rate increased by 18%. Mitochondrial &oxidation of fatty acids decreased (14-2746) and the activity of camitine palmitoyltransferase was reduced (23%). In

11431 w,

Metabolism of postprandial VLDL subfractions in the hypoalphalipoproteinemia and hypertriglyceridemia syndrome Yakichuk JA, Cousins M, Murthy PVN, Ooi TC, Me-

tabolism and Hormone Lab., Div. of Endocrinology and Metabolism, Univ. of Ottawa, 1053 Carling Ave, Ottawa, Ont, Canada Kl Y 4E9

We have examined the chemical composition, mass and retinyl palmitate content of VLDL subfractions (Sf 100-400 and Sf 20100) in fasting and 4- and 8-h postprandial plasma of subjects hypoalphalipoproteinemia and hypertriglyceridemia with (HPAUHTG) and normolipidemic controls. The fat load had

Atherosclerosis X, Montreal, October 1994