Higher Plasma Total Cholesterol Research Articles

Effect of Highly Active Antiretroviral Therapy (HAART) and Hepatitis C Co-Infection on Hyperlipidemia in HIV-Infected Patients: A Retrospective Longitudinal Study

Background: Lipid abnormalities are among the most frequent treatment-limiting adverse events during HAART in HIV-infected individuals. Lipid disturbances have also been associated with hepatitis C virus (HCV) chronic infection in HIV-uninfected participants. HAART-induced lipid abnormalities may then have peculiar features in HIV-HCV co-infected individuals. Purpose: To estimate the prevalence and incidence rates of hypertriglyceridemia and hypercholesterolemia and to identify associated factors in a large clinic population of HIV patients after HAART has been initiated. Design: We performed a retrospective longitudinal follow-up study in a large cohort of HIV patients on their first HAART. Patients and Method: The clinical databases of two major clinical centers in Italy participating in the MASTER study were merged. Treatment-emerging metabolic disorders in patients on their first HAART regimen (PI-based or NNRTI-based) who were stable for at least 4 months were prospectively analyzed by baseline parameters, drug regimens, and viroimmunological outcome of therapy. Follow-up was continued for 24 months or until drug discontinuation, whichever came first. Results: Two hundred and eighty two (282) HIV-infected patients undergoing HAART (203 PI + 79 NNRTI; 65 including stavudine [d4T]) met inclusion criteria and were enrolled in the study from 1997 to 2002. Mean follow-up was 18.5 ± 6.7 months. After HAART had been initiated, a statistically significant mean increase in total cholesterol over time was observed in comparison to baseline (p < .0001), without difference between treatment groups (PI vs. NNRTI, with or without d4T). In the univariate analysis, predictive factors for HAART-induced hypercholesterolemia were baseline total plasma cholesterol and triglycerides values and CD4+ cell count differential increase over time, while a negative correlation was found with zalcitabine-including regimens and baseline HCV seropositivity. At multivariate analysis, only high baseline total plasma cholesterol and triglycerides values retained their predictive value and baseline HCV seropositivity was significantly associated with lower increase in total cholesterol values under HAART, regardless of treatment groups (p < .001). Conclusion: HCV co-infection is an independent factor preventing the emergence of treatment-limiting total cholesterol increase under any HAART regimen, possibly reflecting impaired total cholesterol synthesis in the liver or total cholesterol hypercatabolism. On the contrary, no HCV influence on triglycerides plasma levels was noted. Our data do not suggest any favoring role of specific treatment or drugs (PI and/or d4T) on total cholesterol and triglycerides increase under HAART.

Effect of Highly Active Antiretroviral Therapy (HAART) and Hepatitis C Co-Infection on Hyperlipidemia in HIV-Infected Patients: A Retrospective Longitudinal Study

Background: Lipid abnormalities are among the most frequent treatment-limiting adverse events during HAART in HIV-infected individuals. Lipid disturbances have also been associated with hepatitis C virus (HCV) chronic infection in HIV-uninfected participants. HAART-induced lipid abnormalities may then have peculiar features in HIV-HCV co-infected individuals. Purpose: To estimate the prevalence and incidence rates of hypertriglyceridemia and hypercholesterolemia and to identify associated factors in a large clinic population of HIV patients after HAART has been initiated. Design: We performed a retrospective longitudinal follow-up study in a large cohort of HIV patients on their first HAART. Patients and Method: The clinical databases of two major clinical centers in Italy participating in the MASTER study were merged. Treatment-emerging metabolic disorders in patients on their first HAART regimen (PI-based or NNRTI-based) who were stable for at least 4 months were prospectively analyzed by baseline parameters, drug regimens, and viroimmunological outcome of therapy. Follow-up was continued for 24 months or until drug discontinuation, whichever came first. Results: Two hundred and eighty two (282) HIV-infected patients undergoing HAART (203 PI + 79 NNRTI; 65 including stavudine [d4T]) met inclusion criteria and were enrolled in the study from 1997 to 2002. Mean follow-up was 18.5 ± 6.7 months. After HAART had been initiated, a statistically significant mean increase in total cholesterol over time was observed in comparison to baseline (p < .0001), without difference between treatment groups (PI vs. NNRTI, with or without d4T). In the univariate analysis, predictive factors for HAART-induced hypercholesterolemia were baseline total plasma cholesterol and triglycerides values and CD4+ cell count differential increase over time, while a negative correlation was found with zalcitabine-including regimens and baseline HCV seropositivity. At multivariate analysis, only high baseline total plasma cholesterol and triglycerides values retained their predictive value and baseline HCV seropositivity was significantly associated with lower increase in total cholesterol values under HAART, regardless of treatment groups (p < .001). Conclusion: HCV co-infection is an independent factor preventing the emergence of treatment-limiting total cholesterol increase under any HAART regimen, possibly reflecting impaired total cholesterol synthesis in the liver or total cholesterol hypercatabolism. On the contrary, no HCV influence on triglycerides plasma levels was noted. Our data do not suggest any favoring role of specific treatment or drugs (PI and/or d4T) on total cholesterol and triglycerides increase under HAART.

Assessment of therapy in goitrous goats through some cardiac function tests

Of eight clinically endemic goitrous goats procured locally, six were treated with sodium thyroxine at 0.2 mg per day per goat orally for 100 days. Histopathology of heart in two untreated and two treated goats revealed extensive fatty vacuolization of myocardial fibers in the former group, which was replaced by granularity in the latter group. There was higher plasma total cholesterol and lipids in goitrous goats (293.67±11.93 and 915.51±81.0 mg/dl, respectively) compared to thyroxine treated animals (97.50±7.78 and 528.54±64.3 mg/dl, respectively). Plasma thyroxine and triiodothyronine levels were lower (3.06±0.53 μg/dl and 125.98±33.94 ng/dl, respectively) in goitrous goats than treated goats (8.62±0.71 μg/dl and 209.24±7.84 ng/dl, respectively). Goitre was also accompanied by severe hypoglycemia. Plasma AST enzyme activity declined while lactate dehydrogenase (LDH) activity increased following treatment. Plasma sodium and potassium levels also became significantly improved with the treatment. Electrocardiographic (ECG) data suggested significant improvement in ‘R’ wave amplitude, ‘PQ’ interval, normalization of flattened ‘P’ wave and heart rate post-treatment. The results suggested overall improvement in cardiovascular functions following thyroxine therapy of goitrous goats.

Effects of fluvastatin on plasma lipid abnormalities in hemodialysis patients with chronic renal failure

Fluvastatin, an HMG-CoA reductase inhibitor, was administered at a dosage of 20 mg/day for 24 weeks to 11 hemodialysis patients with a high plasma total cholesterol (TC) level (> or = 220 mg/dl). Serum lipids, apolipoprotein, and malondialdehyde (MDA) levels were measured every 12 weeks. After 24 weeks of fluvastatin administration, the TC level had decreased by 10.5% (238 +/- 15 mg/dl-->203 +/- 25 mg/dl), the low density lipoprotein cholesterol (LDL-C) level had decreased by 16.2% (142 +/- 32 mg/dl-->119 +/- 26 mg/dl), and the HDL-C level had increased by 23.4% (47 +/- 15 mg/dl-->58 +/- 19 mg/dl). These changes were statistically significant and resulted in a reduction of the atherogenic index (AI: TC-HDL-C/HDL-C). The triglyceride (TG) level did not change significantly. The apolipoprotein A1 level increased by 9.1% (121 +/- 22 mg/dl-->132 +/- 20 mg/dl) and the apolipoprotein B level decreased by 20.2% (114 +/- 25 mg/dl-->91 +/- 20 mg/dl). The MDA level also decreased significantly (1.16 +/- 0.92 nmol/ml-->0.58 +/- 0.38 nmol/ml). No particular side effects were observed during the 24 weeks of fluvastatin administration. In conclusion, fluvastatin may play an important role in preventing significant oxidative stress and was shown to be safe and effective in reducing the TC, LDL-C, MDA and AI levels in dialysis patients with hypercholesterolemia. The possibility that this improvement in the plasma lipid profile of dialysis patients may decrease atherogenic complications requires further investigation, including long-term clinical observations.

Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia

Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH 2-terminal domain of SREBP-2 that binds and activates the promoters of SREBP-2-regulated genes including the genes encoding the low-density lipoprotein (LDL) receptor, 3-hydroxymethyl-3-glutaryl-(HMG-)CoA-synthase, and HMG-CoA-reductase. Thus, SREPB-2 gene activation leads to enhanced cholesterol uptake and biosynthesis. A novel protein polymorphism (SREBP-2-595A/G) discovered in the regulatory domain of human SREBP-2 was investigated regarding its impact on cholesterol homeostasis. In human embryonic kidney (HEK)-293-cells, the cleavage-rate of the SREBP-2-595A-isoform was slightly decreased compared to that of the SREBP-2-595G-isoform. Since cleavage of SREBP-2 activates the LDL receptor-mediated uptake of plasma cholesterol, we hypothesized the LDL receptor-mediated uptake to be decreased in homozygous SREBP-2-595A-carriers and thus, plasma total cholesterol (TC) to be higher than in SREBP-2-595G-carriers. Multiple linear regression analysis of population samples from Switzerland ( N=1334) and Israel ( N=923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC ( P=0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (ΔTC=1.05 mmol/l, 14.4%; P=0.002; N=477), but absent in normocholesterolaemic subjects (ΔTC=0.06 mmol/l, 1.4%; P=0.334; N=1780). In summary, a slightly but constantly decreased cleavage-rate of the SREBP-2-595A-isoform compared to that of the SREBP-2-595G-isoform may lead to a reduced transcriptional activation of the LDL receptor-gene weakening the SREBP-mediated compensation mechanisms, and may, therefore, be a critical factor in the development of polygenic hypercholesterolaemia.

Genetic Dissection of Familial Combined Hyperlipidemia

Familial combined hyperlipidemia (FCHL) is the most common genetic hyperlipidemia in man. FCHL is characterized by familial clustering of hyperlipidemia and clinical manifestations of premature coronary heart disease, i.e., before the age of 60. Although FCHL was delineated about 25 years ago, at present the FCHL phenotype and its complex genetics are not fully understood. Initially, the familial aggregation of high plasma total cholesterol and triglyceride levels, with a bimodal distribution of triglycerides, was taken as evidence of a dominant mode of inheritance. However, it is now clear that the genetics of FCHL is more complex, and it has been suggested that FCHL is heterogeneous. Several approaches can be taken to identify genes contributing to the disease phenotype in complex genetic disorders either by studying the disease in the human situation or by using animal models. Recent reports have shown that a combination of genetic linkage studies, association studies, and differential gene expression studies provides a useful tool for the genetic dissection of complex diseases. Therefore, the genetic strategies that will be used to dissect the genetic background of FCHL are reviewed.

APO E gene and gene-environment effects on plasma lipoprotein-lipid levels.

Apolipoprotein E (apo E) is important in plasma lipid metabolism and is a component of several plasma lipoprotein-lipid particles. Three major apo E isoforms are encoded by three common alleles at the APO E locus. The E2 allele is associated with lower and the E4 allele with higher total plasma cholesterol and LDL cholesterol levels compared with the E3 allele. Available data generally indicate that APO E2, and possibly E3, genotype individuals reduce plasma total and low-density lipoprotein (LDL) cholesterol levels more than APO E4 individuals with statin therapy. Some evidence also indicates that APO E2 individuals are more likely to respond favorably to gemfibrozil and cholestyramine. On the other hand, it appears that with probucol, APO E4 genotype individuals may improve plasma lipoprotein-lipid profiles more than APO E3 individuals. APO E2 and E3 genotype perimenopausal women appear to improve plasma lipoprotein-lipid profiles more with hormone replacement therapy than APO E4 women. On the other hand, low-fat diet interventions tend to reduce plasma LDL cholesterol and, perhaps, plasma total cholesterol levels more in APO E4 than in APO E2 or E3 individuals. Both cross-sectional and longitudinal studies generally indicate that APO E2 and E3 individuals improve plasma lipoprotein-lipid profiles more with exercise training than APO E4 individuals. Although these data are hardly definitive, they lend strong support for the possibility that in the near future individuals will be directed to what might be their optimal therapy for improving plasma lipoprotein-lipid profiles and cardiovascular disease risk based partially on APO E genotype.

An uncoupling protein 3 gene polymorphism associated with a lower risk of developing Type II diabetes and with atherogenic lipid profile in a French cohort.

The UCP2-UCP3 gene region has been previously associated with obesity and diabetes. In a large representative cohort of Northern France (MONICA project), we studied the effect of a recently reported C/T polymorphism located in the 5' sequences of the UCP3 gene on anthropometric measurements and lipid profile. We also examined the association of this polymorphism with obesity and Type II (non-insulin-dependent) diabetes mellitus. The -55 C/T polymorphism of the UCP3 gene has been genotyped in 1155 subjects from the MONICA project. Association studies were done with diabetes, obesity and related phenotypes. Results were ascertained in a second cohort of well-characterized Type II diabetic and control subjects. The variant T allele was associated with a decreased risk of developing Type II diabetes. Frequencies of the T allele were 13.3% compared with 22%, p = 0.04, in the diabetic and control groups, respectively. This observation was confirmed in the second cohort of French Type II diabetic (n = 171) and control (n = 124) subjects: 17.8% compared with 25%, p = 0.03. Moreover, subjects bearing the TT genotype had higher plasma total cholesterol and LDL-cholesterol concentrations (p = 0.0006 and p = 0.001, respectively) than subjects bearing wild or heterozygous genotypes. The UCP3 -55 C/T polymorphism was associated with a higher atherogenic profile and modified the risk for the development of Type II diabetes.

Relationship between obesity, total plasma cholesterol and blood pressure in male adults

I investigated the relationship between the percentage of body fat, Body Mass Index (BMI) and total plasma cholesterol and blood pressure. The percentage of body fat was measured by the bioelectrical impedance method. The subjects investigated were 2,955 men aged from 23 to 59 years, who were working in a company making machinery. They were divided into four groups as follows. The normal group were within the normal BMI range (< 24) and body fat percentage range (< 20%). The seemingly obese group were over the normal BMI (> or = 24) and normal percentage of body fat range. The occult obesity group were within the normal BMI range and over the normal percentage of body fat range (> or = 20%). The obese group were over the BMI and percentage of body fat range. In each group, those who had high total plasma cholesterol and blood pressure were counted. The number of those who had high total plasma cholesterol was significantly larger in the obese group than in the seemingly obese group and the normal group, and larger in the occult obesity group than in the seemingly obese group and normal group and larger in the seemingly obese group than in the normal group. The number of those who had high systolic blood pressure was significantly larger in the obese group than in the occult obesity group, the seemingly obese group and the normal group, larger in the occult obesity group than in the normal group and larger in the seemingly obese group than in the normal group. The number of those who had high diastolic blood pressure was significantly larger in the obese group than in the occult obesity group, and the seemingly obese group and the normal group, larger in the occult obesity group than in the normal group, and larger in the seemingly obese group than in the normal group. These results suggest that measurement of percent body fat is useful in preventing adult diseases in employees with a high percentage of body fat, but who show no sign of abnormality in medical examinations, and those who are considered to be obese according to their BMI or percentage of body fat have a high risk of adult diseases.

Characterization of the bile acid profile in developing male and female hamsters in response to dietary cholesterol challenge

The Syrian golden hamster is a frequently used model to study cholesterol and bile acid metabolism as well as cholesterol-induced cholelithiasis. However, diet-induced gallstones seem limited to young male hamsters of certain strains that develop depressed cholate/chenodeoxycholate bile acid ratios. To further elucidate gender and age specific aspects of cholesterol and bile acid metabolism, i.e. a possible age-related bile acid/gallstone relationship, plasma and biliary lipids and bile acid composition were analyzed in male and female hamsters under various physiological conditions of age and diet, the latter formulated with and without dietary cholesterol. During normal development (no cholesterol challenge) the percentage of cholic acid decreased while chenodeoxycholate increased, the shift being more pronounced in males. Furthermore, female hamsters had higher total plasma cholesterol than in males, while hepatic and biliary lipids did not differ. When challenged with excessive dietary cholesterol, female hamsters again developed significantly higher total plasma and hepatic cholesterol concentrations. Biliary lipids and cholesterol gallstone incidence revealed a significant gender effect with male hamsters developing a higher lithogenic index and more gallstones (cholesterol and pigment stones) than females. Female hamsters revealed a lower percentage of chenodeoxycholate and a higher percentage of cholate resulting in a more protective, higher cholate/cheno ratio (1.5±1.0) than in males (1.0±0.2). In summary, the bile acid pattern in developing and cholesterol-fed hamsters renders females less susceptible to gallstones, in part because they maintain more favorable biliary lipid and bile acid profiles, characterized by lower molar percentages of biliary cholesterol and chenodeoxycholate.

Epitopes for chicken monoclonal antibodies in spleens of selected Japanese quail lines

A line of Japanese quail selected for high plasma cholesterol is highly susceptible to diet-induced atherosclerosis. Lymphocyte epitopes recognized by mouse anti-chicken monoclonal antibodies (c-mAb), TCR-1, TCR-2, TCR-3, CD-3, CD-4, CD-8, and BU-1a/b were reacted with spleens from quail selected for high (HL) and low (LL) plasma total cholesterol and their nonselected controls (CL). Cross reactivity to c-mAb and effect of line and gender were immunohistochemically evaluated. Chicken spleens were positive controls. Quail were immunologically stimulated with either sheep red blood cells (SRBC) or Brucella abortus 2 weeks before spleens were removed. Quail spleen epitopes of all lines recognized TCR-3 and CD-8 c-mAb, but no other c-mAb. Number of reacting cells and staining intensity to the TCR-3 c-mAb were greater in the HL than in the LL regardless of the stimulating Ag or dose used. For the CD-8 c-mAb, there were no differences among lines in birds receiving SRBC. In B. abortus-immunized birds, sex×line interactions indicated that males of the HL and CL had lower responses than females but LL males were not different than females. TCR-3 and CD8 c-mAb may be useful in studying immunological mechanisms for atherosclerosis in Japanese quail.

Testosterone and other anabolic steroids as cardiovascular drugs.

There has been much interest in the effect of sex hormones on cardiovascular risk factors and as a therapeutic modality in both men and women. In this article, testosterone is considered as a possible therapy for cardiovascular disease. It has been shown that the level of serum testosterone decreases in men as they age. Healthy men with low testosterone levels have increased cardiovascular risk factors, including high fasting and 2-hour plasma glucose, serum triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol, and apo A-I lipoprotein. Injections of testosterone to raise the levels to midnormal range have been shown to decrease total cholesterol and LDL cholesterol, while increasing high-density lipoprotein (HDL) cholesterol. Testosterone affects the clotting system by increasing thromboxane A (2) receptor activity and platelet aggregability. Testosterone has also been shown to augment the fibrinolytic system and antithrombin III activity. In men, testosterone has been shown to have antianginal effects, and endogenous levels have an inverse relationship to systolic blood pressure. Testosterone can be given in oral, injectable, pellet, and transdermal patch forms. There may be a role in administering testosterone to return men to normal physiologic range who have low serum levels. This treatment increases the risk of prostatic cancer, benign prostatism, erythrocytosis, and edema. No long-term studies of the effects of long-term testosterone replacement have been undertaken, so it is difficult to recommend this treatment as yet, but it is being considered as a therapy for augmenting skeletal muscle strength in patients with congestive heart failure.

Maternal Dietary Protein Deficiency Decreases Nitric Oxide Synthase and Ornithine Decarboxylase Activities in Placenta and Endometrium of Pigs During Early Gestation

Little is known about the mechanism responsible for retarded placental and fetal growth induced by maternal dietary protein malnutrition. On the basis of the recent finding that nitric oxide (NO) and polyamines (products of L-arginine) play an important role in embryonic and placental development, the present study was designed to determine whether protein deficiency decreases placental and endometrial activities of NO synthase (NOS) and ornithine decarboxylase (ODC) (the first and key regulatory enzyme in polyamine synthesis). Primiparous gilts selected genetically for low or high plasma total cholesterol concentrations (low line and high line, respectively) were mated and then fed 1.8 kg/d of isocaloric diets containing 13% or 0.5% crude protein. At d 40 or 60 of gestation, they were hysterectomized, and placenta and endometrium were obtained for incubations, NOS and ODC assays, and measurements of free amino acids and polyamines. Maternal dietary protein restriction decreased arginine and ornithine concentrations, constitutive and inducible NOS activities and NO production, as well as ODC activity and polyamine concentrations in placenta and endometrium of both lines of gilts. Placental NO synthase activity and NO generation were lower in high line gilts than in low line gilts. ODC activities and polyamine concentrations in placenta and endometrium were decreased at d 60 compared with d 40 of gestation. These changes in placental and endometrial synthesis of NO and polyamines during early gestation may be a mechanism responsible for reduced placental and fetal growth in protein-deficient gilts and for altered conceptus development in high line gilts.

Effect of neonatal dietary cholesterol deprivation in pigs with genetically high or low plasma cholesterol on plasma lipids and early atherogenesis

Sixty-eight neonatal female pigs from populations selected for high (HG) or low (LG) plasma total cholesterol were used in two experiments to test the hypothesis that dietary cholesterol deprivation during the first 4 or 8 weeks of postnatal life increases plasma total cholesterol and exacerbates early aortic atherogenic lesions following free access to a high fat (15 g/100g)-high cholesterol (0.5 g/100g) diet from 4 or 8 weeks to 5 or 6 mo of age. Pigs were removed from their dam at one d of age and given free access to a modified sow-milk replacer diet containing 0 or 0.5% crystalline cholesterol. In each experiment, half of the HG and LG pigs were fed a sow-milk replacer diet containing 0 cholesterol and half were fed the same diet containing 0.5% added cholesterol. All pigs (except HG and Lg pigs in experiment 2 deprived of cholesterol throughout) were fed a 15% fat-0.5% cholesterol diet from 57 d to 6 mo (experiment 1) or 5 mo (experiment 2) of age. Overall total cholesterol and high density lipoprotein cholesterol were greater in HG than in LG pigs (P<0.01) and less in pigs fed no cholesterol than in those fed cholesterol neonatally (P<0.05) in both experiments. Nevertheless, dietary cholesterol deprivation neonatally in either HG or LG pigs did not affect the incidence or severity of aortic myogenic fiber degeneration, considered to be an early stage of atherogenic lesion development in these experimental swine. It is concluded that early aortic atherogenic lesions induced in young adult female HG and LG pigs by a high dietary cholesterol challenge during the postweaning period are not exacerbated by dietary cholesterol deprivation in neonatal life.

Differences in response between 18 carbon fatty acids and [formula omitted] carbon saturated fatty acids on plasma cholesterol in Guinea pigs

Male guinea pigs were fed four different diets rich in lauric plus myristic (LM), stearic (ST), oleic (OL) or linoleic (LN) fatty acids to compare the effects of 18 carbon fatty acids with different degrees of saturation with 12 14 carbon saturated fatty acids on hepatic cholesterol metabolism. Animals fed the LM diet had 76–100% higher plasma total cholesterol and apo B concentrations than those fed ST, OL or LN diets (P < 0.001). The hypercholesterolemic effects of LM intake were associated with concomitant increases in plasma LDL cholesterol. No difference in plasma VLDL and HDL cholesterol or triacylglycerol (TAG) concentrations were observed among the four groups. VLDL + IDL and LDL composition were significantly altered by dietary fat saturation. The relative proportion of free cholesterol was higher and TAG lower in VLDL of animals fed the LM diet. Cholesteryl ester concentrations in LDL decreased as chain length and saturation of fatty acids increased in the order LN<OL<ST<LM. Hepatic cholesterol was not affected by dietary fatty acids. In contrast hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity was lower in animals fed the LM diet while no differences in acyl CoA cholesterol:acyltransferase activity were observed among dietary groups. Plasma lecithin:cholesterol acyl:transferase activity was higher in animals fed LM and ST diets compared to those fed OL and LN diets (P < 0.01). Hepatic apo B E receptor number was highest in animals fed LN diet and intake of ST and OL diets resulted in higher hepatic apo B E receptor number compared to animals fed LM diets (P < 0.001). These studies indicate that the different fatty acids affect plasma cholesterol levels by alterations on hepatic cholesterol metabolism. While intake of stearic, oleic and linoleic acids result in similar plasma cholesterol levels, short chain fatty acid intake results in hypercholesterolemia in guinea pigs.

Maternal Dietary Protein Deficiency Decreases Amino Acid Concentrations in Fetal Plasma and Allantoic Fluid of Pigs

This study was conducted to test the hypothesis that maternal dietary protein deficiency decreases amino acid availability to the fetus, thereby contributing to retarded fetal growth. Primiparous gilts selected genetically for low or high plasma total cholesterol concentrations (low line and high line, respectively) were mated, and then fed 1.8 kg/d of isocaloric diets containing 13% or 0.5% crude protein. At d 40 or 60 of gestation, they were hysterectomized, and maternal and fetal blood samples as well as amniotic and allantoic fluids were obtained for analyses of amino acids, ammonia and urea. Dietary protein restriction decreased (P < 0.05) the following: 1) maternal plasma concentrations of urea at d 40 and 60 of gestation; 2) fetal plasma concentrations of alanine, arginine, branched-chain amino acids (BCAA), glutamine, glycine, lysine, ornithine, proline, taurine, threonine and urea at d 60 of gestation; 3) amniotic and allantoic fluid concentrations of urea at d 40 and 60 of gestation; and 4) allantoic fluid concentrations of alanine, arginine, BCAA, citrulline, cystine, glycine, histidine, methionine, proline, serine, taurine, threonine and tyrosine at d 40 of gestation, in gilts of both genetic lines. At d 60 of gestation, protein deficiency decreased (P < 0.05) allantoic fluid concentrations of arginine, cystine, glycine, taurine and tyrosine in low line gilts and of cystine, glutamine, ornithine, serine, taurine and tyrosine in high line gilts. Low line and high line gilts also differed remarkably in allantoic fluid concentrations of arginine, glutamine, ornithine and ammonia at d 40 and 60 of gestation. Our results suggest the following: 1) protein-deficient gilts maintain maternal plasma concentrations of amino acids by mobilizing maternal protein stores and decreasing oxidation of amino acids during the first half of gestation; 2) protein deficiency may impair placental transport of amino acids from the maternal to the fetal blood; and 3) low line and high line gilts differ in fetal amino acid metabolism. Decreases in concentrations of the essential and nonessential amino acids in the fetus may be a mechanism whereby maternal dietary protein restriction results in fetal growth retardation.

Alleles of the cholesterol 7 alpha-hydroxylase (CYP7) gene in pigs selected for high or low plasma total cholesterol.

Crossbred pigs were selected for high (HTC) or low (LTC) plasma total cholesterol (TC). Pigs from the seventh (n = 51) and eighth (n = 92) generations were used to determine restriction fragment length polymorphisms (RFLP). Using TaqI restriction enzyme digestion, the frequencies of two alleles (2.8- or 5.0-kb fragments) of the cholesterol 7 alpha-hydroxylase (CYP7) gene were determined in the two populations as a potential indicator of TC concentration at 8 weeks of age. Only the 2.8-kb fragment allele was present in the 26 HTC pigs tested in Generation 7. In the LTC pigs both the 2.8- and 5.0-kb alleles were present in 12 pigs, and only the 5.0-kb allele was present in 13 pigs. The allele frequencies of the 2.8 and 5.0 fragments, respectively, were .26 and .74 in LTC pigs and 1.00 and 0 in HTC pigs. There was an association (P < .001) between the 5.0- and 2.8-kb CYP7 alleles, respectively, and low and high TC concentrations. In Generation 8, all HTC pigs were homozygous for the 2.8-kb allele. The 5.0 kb allele was present in all LTC pigs tested and was homozygous in 57% of LTC pigs. Mean plasma TC was 105.0 mg/dl in 30 pigs homozygous for the 2.8-kb allele in Generation 8; means for LTC pigs were 53.5 and 60.4 mg/dl in 35 pigs homozygous for the 5.0-kb allele and in 27 heterozygous pigs, respectively. High TC was associated with the presence of the 2.8-kb allele, and low TC was associated with the presence of the 5.0-kb allele in both Generations 7 and 8. We conclude that TaqI RFLP analysis of the CYP7 gene is a reliable indicator for TC in these swine.

Divergent concentrations of plasma metabolites in swine selected for seven generations for high or low plasma total cholesterol.

It was reported previously that selection for high (HG) or low (LG) plasma total cholesterol (TC) at 8 wk of age in a composite four-breed swine population resulted after four generations in divergent mean concentrations in the selected lines. The data revealed a significant positive correlation between body weight (BW) and TC concentration at 8 wk of age and differential responses in litter size, backfat depth, and carcass length at 6 mo of age. We report here the relationship between plasma TC concentration and other plasma traits related to growth and metabolism in the seventh generation of selection in these two lines of pigs. We measured plasma concentrations of TC, HDL cholesterol (HDL-C), triglycerides (TG), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), urea nitrogen (urea N), and three transaminases (alanine aminotransferase, ALT; aspartate aminotransferase, AST; gamma glutamyltransferase, GGT) in seventh-generation male and female pigs at 8 wk of age. Birth weight (1.48 vs 1.38 kg), 8 wk BW (14.85 vs 12.00 kg), TC (116.8 vs 63.6 mg/dL), HDL-C (43.9 vs 25.5 mg/dL), TG (50.5 vs 33.0 mg/dL), and ALP (78.3 vs 44.9 units/L) were higher (P < .01) in HG than in LG pigs, whereas ALB (3.2 vs 3.4 g/dL), ALT (43.0 vs 45.9 units/L), and AST (53.0 vs 62.2 units/L) were lower in HG than in LG pigs (P < .05). At 8 wk, overall plasma TC concentration was correlated with BW (r = .34, P < .01) and with ALP (r = .23, P < .05) but was not related to ALT, AST, or GGT. Plasma TP urea N, and GGT were unaffected by genetic line on sex. We conclude that the difference between HG and LG pigs in TC concentration in generation 4 at 8 wk of age has persisted but not broadened in pigs of generation 7, that changes in plasma ALP, ALT, and AST may have occurred in response to selection for high or low plasma TC, and that ALP is correlated with plasma TC concentration.

Dietary cholesterol metabolism in Japanese quail lines selected for plasma cholesterol levels.

Dietary cholesterol metabolism was studied, using a single dose of emulsion, per os (test meal), in lines of Japanese quail that were divergently selected for high (HL) and low (LL) plasma total cholesterol. The meal contained [3H] cholesterol, [14C] beta-sitosterol, unlabeled cholesterol, triolein, and bile salt. Recovery of the nonabsorbable beta-sitosterol in the excreta permitted determination of the percentage of cholesterol absorbed. The amounts of [3H] in the plasma, egg yolks, and the excreta neutral and acid sterols were determined. A line-x-time interaction for [3H] in plasma indicated that the level of plasma cholesterol derived from the test meal declined more rapidly in the LL than in the HL. The higher [3H] detected in the excreta acidic sterols of the LL 12 hr after the test meal indicated that bile acid excretion of cholesterol was greater in the LL than in the HL. There were no differences in cholesterol absorption between lines or sexes. Cumulative [3H] radioactivity in the eggs over 18 days following the test meal was higher in the HL yolks; however, this line effect was due to the greater number of eggs produced by the HL. Thus, one of the mechanisms by which the LL maintains low plasma cholesterol levels is by an enhanced excretion of bile acid compared with the HL. The data also suggest that the more severe atherogenic effect of dietary cholesterol observed in the HL could be, in part, due to the longer residence time of cholesterol in circulation.

Dietary Cholesterol Effects on Plasma and Yolk Cholesterol Fractions in Selected Lines of Japanese Quail

Japanese quail from lines that had been divergently selected for high (HL) or low (LL) plasma total cholesterol and their unselected control line (CL) were fed an all vegetable diet to which 0 or 0.5% crystalline cholesterol were added. Relationships between plasma and yolk cholesterol fractions were examined at 10, 14, and 18 wk of age, which followed 2, 6, and 10 wk consumption of the cholesterol-enriched diet, respectively. Unesterified cholesterol (UC) and cholesteryl esters (CE) in plasma and yolk were analyzed using HPLC. There were no consistent correlations between yolk and plasma for UC, individual CE, total esterified cholesterol (EC), or total cholesterol in the selected lines at ages tested, whether or not 0.5% cholesterol was added to the diet. Cholesterol concentrations in milligrams per gram of yolk and in milligrams per yolk were higher in the HL than the LL at 10 and 14, but not at 18 wk of age. Yolk weights of the HL females increased from 10 to 18 wk of age, whereas those of the LL did not. Cholesterol concentrations in the LL yolks continued to increase over time, however the increases in yolk weight in the HL were not accompanied by proportional increases in cholesterol deposition in the yolk, leading to a dilution of concentration of cholesterol fractions in the HL yolk. Dietary cholesterol increased egg production rate in the selected lines but did not increase the cholesterol content of the yolk.