Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs.

Aiello RJ, Nevin DN, Ebert DL, Uelmen PJ, Kaiser ME, MacCluer JW, Blangero J, Dyer TD, Attie AD.

Department of Biochemistry, University of Wisconsin, Madison 53706.

The Lpb5 apolipoprotein B (apoB) allele occurs in pigs with spontaneous hypercholesterolemia. Low-density lipoprotein (LDL) from these pigs binds to the LDL receptor with a lower affinity and is cleared from the circulation more slowly than control pig LDL. However, the severity of hypercholesterolemia in pigs with the mutant apoB allele is highly variable. This study aimed to determine the metabolic basis for the phenotypic heterogeneity among Lpb5 pigs. Lpb5 pigs were divided into two groups: those with plasma cholesterol greater than 180 mg/dL (Lpb5.1) and those with plasma cholesterol less than 180 mg/dL (Lpb5.2). LDL from both Lpb5.1 and Lpb5.2 pigs was catabolized in vivo and in vitro at a similarly reduced rate. The difference in plasma cholesterol between the two phenotypic groups was in part due to a higher buoyant LDL production rate in Lpb5.1 pigs than in Lpb5.2 pigs. The in vivo LDL receptor status was evaluated by measuring the catabolism of LDL chemically modified to abrogate LDL receptor binding. Approximately 50% of LDL clearance in normal and Lpb5.2 pigs was via the LDL receptor; in Lpb5.1 pigs, 100% of LDL clearance was LDL receptor independent. Quantitative pedigree analysis of the segregation of the plasma cholesterol phenotype suggested that two major gene loci (the apoB locus and a second apparently unlinked locus) contribute to the determination of plasma cholesterol levels in this pig population.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8123646&dopt=Abstract cholesterol




Inhibition of atherosclerosis by dietary pectin in microswine with sustained hypercholesterolemia.

Cerda JJ, Normann SJ, Sullivan MP, Burgin CW, Robbins FL, Vathada S, Leelachaikul P.

Department of Medicine, University of Florida College of Medicine, Gainesville.

Sustained hypercholesterolemia is a known risk factor for development of atherosclerosis. In animal studies, grapefruit pectin fed concurrently with a high-lipid diet inhibits hypercholesterolemia and atherogenesis. The purpose of the present study was to determine if grapefruit pectin affects cholesterol levels and atherogenesis of animals with established hypercholesterolemia. Microswine were fed an atherogenic diet to establish hypercholesterolemia. Plasma cholesterol levels rose rapidly and for 360 days were sustained at levels 6- to 12-fold the normal level. Then, half the microswine, selected at random, were fed a diet in which 3% grapefruit pectin was substituted for cellulose, and the remaining animals received the original diet. Animals were killed 270 days later, and the extent of atherosclerosis was determined. In animals with established hypercholesterolemia, pectin did not lower their cholesterol levels. However, pectin reduced the extent of atherosclerosis in both the aorta and coronary arteries. The mean surface area covered by atherosclerosis in the aorta was 13.6% in the group that did not receive pectin compared with 5.3% in the group that did receive pectin. The mean coronary artery narrowing was 45% without pectin and 24% with pectin. We conclude that pectin may have a direct beneficial effect on atherosclerosis by a mechanism independent of cholesterol levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8124813&dopt=Abstract cholesterol




[Factors affecting serum lipid levels in patients with type 2 diabetes mellitus]

[Article in Slovak]

Tkac I, Tkacova R, Molcanyiova A, Mudrikova T, Takac M.

IV. interna klinika LF UPJS Kosice.

Serum lipid concentrations were assessed in 147 type 2 diabetics. The patients were divided into different sub-groups in order to follow up different factors which could have an impact on serum lipids. The mean total cholesterol concentrations were significantly higher in diabetic women as compared with men. The authors did not reveal significant differences in lipid concentrations between obese and non-obese diabetics. Hypertensive diabetics had higher mean total cholesterol levels and LDL-cholesterol levels, as compared with diabetic patients without hypertension. Patients using oral antidiabetics had significantly higher mean triglyceride levels and lower HDL-cholesterol levels, as compared with insulin-treated diabetics. In a multiple stepwise regression analysis correlated triglycerides with three independent variables: total cholesterol, diastolic blood pressure and inversely with HDL-cholesterol. On the other hand, total cholesterol correlated significantly with triglycerides, HDL-cholesterol and proteinuria/day. To sum up, it may be stated, that the results of the present investigation are consistent with Reaven's concept of the syndrome X, however the cholesterol concentration is affected also by the proteinuria.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8140744&dopt=Abstract cholesterol




Reevaluation and application of the dual-isotope plasma ratio method for the measurement of intestinal cholesterol absorption in the hamster.

Turley SD, Herndon MW, Dietschy JM.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8887.

These experiments systematically evaluated the dual-isotope plasma ratio method for measuring intestinal cholesterol absorption in the hamster. It was found that while the ratio of the 3H- and 14C-labeled cholesterol in the plasma, relative to the respective dose of each that was given, became constant by 72 h after their administration, the percent cholesterol absorption was lower in animals that were fasted before dosing (35.7 +/- 5.5%) than in their fed controls (47.5 +/- 3.7%). Furthermore, the percent absorption found 72 h after dosing varied greatly, depending on whether the intragastric dose of labeled cholesterol was administered in medium chain triglyceride (MCT) oil (46.2 +/- 2.3%), olive oil (63.9 +/- 11.2%), or safflower oil (74.6 +/- 4.5%). The level of absorption was not different between hamsters that had unrestricted (46.3 +/- 1.6%) and restricted (43.8 +/- 2.2%) access to their stools during the 72 h after dosing. Other experiments, using only hamsters in the fed state and MCT oil as the intragastric dosing medium, showed that the percent cholesterol absorption could be made to vary over a wide range using treatments known to produce such effects in humans. Thus, feeding either surfomer, cholestyramine, ursodeoxycholic acid, or CI-976, a new inhibitor of acyl-CoA:cholesterol acyltransferase, significantly blocked cholesterol absorption, whereas the addition of either cholic acid or increasing amounts of oil to the diet had the opposite effect. The modified dual-isotope plasma ratio method described here provides a simpler and more physiologic approach to the routine measurement of cholesterol absorption in the hamster and similar small animal models.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8169536&dopt=Abstract cholesterol




Health-based reference values of the Mini-Finland Health Survey: 2. Cholesterol in total serum and in different lipoprotein fractions.

Maatela J, Marniemi J, Reunanen A, Jarvisalo J, Maki J, Tikkanen MJ.

Research and Development Unit, Social Insurance Institution, Turku, Finland.

The reference values for cholesterol concentrations in the whole serum and in its VLDL, LDL and HDL fractions have been produced based on the data obtained in the Mini-Finland Health Survey. The lipoprotein fractions were separated with ultracentrifugation. The aim was to obtain reference values for the apparently healthy, ambulatory population. Two health-derived criteria were used to select subjects for reference populations: those based on the literature available and those based on the recommendations published by the Committee on Reference Values of the Scandinavian Society for Clinical Chemistry and Clinical Physiology, with slight modifications. The 95% inner reference intervals of total serum cholesterol in all the subjects and in the two selection groups were 4.2-9.0, 4.2-8.4, and 4.2-8.5 mmol l-1 for men, and 4.2-9.4, 4.1-8.6, and 4.2-9.0 mmol l-1 for women, respectively. The corresponding medians were 6.3, 6.2 and 6.2 mmol l-1 in men, and 6.4, 6.0 and 6.1 mmol l-1 in women, respectively. Frequency distribution curves showed clear skewness to the right in VLDL cholesterol and slight skewness in LDL and HDL cholesterol. In women there was a clear rise in total, VLDL and LDL cholesterol after the early middle age, whereas HDL cholesterol was lower in the older age groups. In men the age dependency was not as prominent; total cholesterol levels showed lower levels in older men. Of the background lifestyle factors alcohol consumption, smoking, obesity and physical exercise had negligible associations with total, VLDL, LDL and HDL cholesterol reference intervals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8171269&dopt=Abstract cholesterol




Public cholesterol screening in the previously diagnosed: misuse of resources or beneficial function?

Maiman LA, Greenland P, Hildreth NG, Cox C.

Department of Pediatrics, School of Medicine and Dentistry, University of Rochester, NY.

The attendance of individuals with a previous diagnosis of hyperlipidemia at public cholesterol screenings is often criticized as a misuse of such programs. This study explored the post-screening actions of 811 participants in a cholesterol screening program who had previously been diagnosed with cholesterol elevations and whose blood levels at this screening required further medical referral. We also studied the responses of physicians from whom these subjects sought care. Within five months, 559 of 753 participants completing the survey (74.0%) sought medical follow-up. Physicians retested the blood cholesterol levels of 75.0% of these 559; high-risk screenees were more likely to be retested and to be informed that their levels were elevated than moderate-risk subjects (P < .0001). Physicians increased cholesterol-lowering dietary advice for high-risk subjects (P < .0001) and medication prescriptions for both risk groups (P < .0001). Participants seeking medical care after the screening program had better cholesterol-lowering dietary practices and reported increased regimen compliance (moderate-risk: P = .01; high-risk: P < .0001) than those individuals not obtaining medical follow-up. One year after screening, blood cholesterol levels were 4.5% lower (P = .001) in those complying with referral but were virtually unchanged in noncompliers. Screening program confirmation of high blood cholesterol levels combined with referral appeared to have a positive impact on previously diagnosed screenees. We conclude that there may be merit in including previously diagnosed individuals in cholesterol screening programs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8172727&dopt=Abstract cholesterol




Regulation of serum cholesterol level in middle-aged and elderly men. Relation of cholesterol absorption and synthesis to lipoprotein metabolism.

Gylling H, Strandberg T, Tilvis R, Miettinen TA.

Department of Medicine, University of Helsinki, Finland.

The aim of the present study was to investigate cholesterol absorption and cholesterol and bile acid synthesis and relate these values of kinetics of low-density lipoprotein (LDL) apoprotein (apo) B in 50- and 75-year-old men to find out why and by which mechanism serum cholesterol level decreases with advancing age under normal home-living conditions. The daily calorie, fat, and cholesterol intakes were lower in the 75-year-old men because the physiological requirements of daily energy are reduced in old age. However, absolute body weight was identical in the two groups, indicating isocaloric energy intake. Serum levels of total and LDL cholesterol were insignificant lower but those of LDL apo B significantly lower, so that the LDL cholesterol/apo B ratio was higher in the elderly men. The mean reduction of LDL apo B by 26% (P < .05) in the old men was associated with a 30% (P < .05) decrease in transport rate (TR) and a 3% (P = NS) decrease in removal (FCR) for LDL apo B. However, at the comparable apo B levels, both TR and FCR for apo B were significantly lower in the old than in the younger men. Cholesterol absorption efficiency, bile acid synthesis, fecal neutral and total sterol excretion, and cholesterol turnover but not synthesis were reduced in the elderly men.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8172847&dopt=Abstract cholesterol




Associations of allelic differences at the A-I/C-III/A-IV gene cluster with carotid artery intima-media thickness and plasma lipid transport in hypercholesterolemic-hypertriglyceridemic humans.

Patsch W, Sharrett AR, Chen IY, Lin-Lee YC, Brown SA, Gotto AM Jr, Boerwinkle E.

Department of Medicine, Baylor College of Medicine, Houston, Tex.

Individuals with elevated levels of plasma cholesterol and triglyceride may be at higher risk for coronary artery disease than those with isolated elevations of either cholesterol or triglyceride. Sequence variation in the A-I/C-III/A-IV gene cluster has been implicated in the etiology of some disorders associated with premature atherosclerosis and/or hypertriglyceridemias with or without elevations of cholesterol. This led to the hypothesis that allelic variation at this gene locus alters plasma lipid transport and affects susceptibility for atherosclerosis. The study population, from the Atherosclerosis Risk in Communities (ARIC) Study, consisted of 50 normolipidemic individuals, 48 subjects with elevated plasma cholesterol, 47 subjects with elevated plasma triglyceride, and 123 subjects with both elevated plasma cholesterol and triglyceride who were used to evaluate associations between an Xmn I polymorphic site 2.5 kilobase pairs (kbp) upstream of the structural gene for apolipoprotein (apo) A-I, intimal-medial thickening of the extracranial carotid arteries, and several plasma lipid factors. The relative allele frequencies of the 8.3-kbp allele and the 6.6-kbp allele were .86 and .14, respectively, in the entire study population and did not differ among the lipid phenotypes. In the group with elevated plasma cholesterol and triglyceride, subjects possessing the 6.6-kbp allele exhibited a greater carotid artery intimal-medial thickness (P = .034) and higher plasma levels of apoA-I, high-density lipoprotein (HDL) cholesterol, and HDL3 cholesterol (P < .02) than subjects homozygous for the 8.3-kbp allele. In contrast, subjects with the 6.6-kbp allele displayed lower mean ratios of apolipoproteins C-II to C-III, C-II to A-IV and E to A-IV in plasma (P < .05) and a lower mean ratio of apolipoprotein C-II to C-III in the triglyceride-rich lipoproteins (P = .026). Sequence variation in or near the genes encoding apolipoproteins A-I, C-III, and A-IV may therefore identify a group of hypercholesterolemic-hypertriglyceridemic persons who are at higher risk for atherosclerosis than others with the same lipoprotein phenotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8199177&dopt=Abstract cholesterol




Familial and diet-induced hypercholesterolemia in swine. Lipid, ApoB, and ApoA-I concentrations and distributions in plasma and lipoprotein subfractions.

Hasler-Rapacz JO, Nichols TC, Griggs TR, Bellinger DA, Rapacz J.

Department of Genetics, University of Wisconsin, Madison 53706.

Low levels of high-density lipoproteins (HDLs) may constitute an independent risk factor that may be as important as elevated low-density lipoproteins (LDLs) in coronary artery disease (CAD). Concentrations and distributions of lipids, apolipoprotein (apo) B, and apoA-I in the plasma and lipoprotein subfractions of two groups of swine, one with familial hypercholesterolemia (FHC) and the other with diet-induced hypercholesterolemia (DHC), were examined. Normolipidemic (NL) animals served as controls. All pigs carried the Lpb5 apoB mutation, which is known to influence the formation of atherosclerotic lesions. Mean concentrations of serum total cholesterol in NL, DHC, and FHC were 80.0 +/- 9.3, 774.3 +/- 54.5, and 316.5 +/- 36.1 mg/dL, respectively; HDL cholesterol (HDL-C), 33.5 +/- 1.9, 137.0 +/- 9.9, and 22.3 +/- 2.2 mg/dL; triglycerides, 33.0 +/- 16.3, 40.3 +/- 11.7, and 56.8 +/- 7.2 mg/dL; apoB, 35.7 +/- 3.1, 142.0 +/- 4.8, and 169.3 +/- 13.9 mg/dL; and apoA-I, 62.4 +/- 9.3, 170.9 +/- 6.9, and 42.6 +/- 4.8 mg/dL. The distributions of total cholesterol, apoB, and apoA-I in plasma lipoprotein subfractions were also examined. Compared with NL, FHC had fourfold and 4.7-fold increases in total cholesterol and apoB, respectively, distributed in the lower densities (d < 1.043 g/mL), and low HDL-C and apoA-I levels, resulting in a high total cholesterol/HDL-C ratio (14.4:1) and elevated triglyceride levels. DHC was characterized by 10-fold and fourfold increases in total cholesterol and apoB, respectively, resulting in an LDL particle highly enriched in cholesterol, a fourfold increase of HDL-C, an almost threefold increase in apoA-I, and a normal triglyceride level.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8199183&dopt=Abstract cholesterol