Cholesterol Journal Articles

Record 7401 to 7420

Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy
Blair, S. N., D. M. Capuzzi, et al. (2000), Am J Cardiol 86(1): 46-52.
Abstract: This study compares the effect of plant stanol ester spread with a placebo spread on cholesterol in patients taking statin therapy, but who still had elevated low-density lipoprotein (LDL) cholesterol. This was a randomized, double-blind, placebo-controlled clinical trial, with 67 women and 100 men with LDL cholesterol >/=130 mg/dl and triglycerides

Independence of myocardial disease in the JCR:LA-corpulent rat on plasma cholesterol concentration
Russell, J. C., D. G. Koeslag, et al. (1991), Clin Invest Med 14(4): 288-95.
Abstract: The JCR:LA-corpulent rat is one of the strains incorporating the corpulent (cp) gene. Animals homozygous for the cp gene are obese, insulin-resistant and hyperlipidemic. Corpulent males, but not females or lean rats, spontaneously develop atherosclerotic and ischemic myocardial lesions. Administration of clofibrate to corpulent male rats reduced the plasma cholesterol ester concentration by 50% to that of lean controls rats. Unesterified cholesterol was slightly raised by the treatment. The markedly raised triglyceride concentrations were lowered modestly (from 282 to 220 mg/100 ml), but significantly in young rats and more markedly (from 305 to 136 mg/100 ml) in 9-month-old chronically treated rats. Apolipoproteins A-1 and E were reduced and Apo B increased by clofibrate treatment. Fasting plasma glucose and insulin concentrations were not altered nor was there any change in the impaired glucose tolerance in clofibrate-treated rats. Myocardial lesion frequency was also not reduced by clofibrate treatment. These results are consistent with others that showed inhibition of myocardial lesion formation only when the plasma insulin levels were reduced. Thus myocardial lesion formation in this strain of rats, while probably dependent upon the presence of hypertriglyceridemia, is most critically dependent upon hyperinsulinemia.

Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model
Mann, K. M., F. E. Thorngate, et al. (2004), Hum Mol Genet 13(17): 1959-68.
Abstract: The APOE epsilon4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more epsilon4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE epsilon2 and epsilon3 alleles, however, appear to be protective against the effects of epsilon4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Abeta pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Abeta metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Abeta levels in a genomic-based model of AD, irrespective of genotype. These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS, and that the altered levels of cholesterol and APOE in these mice are insufficient to influence Abeta metabolism in a mouse model of Alzheimer's disease.

Independent regulation of cholesterol incorporation into free apolipoprotein-mediated cellular lipid efflux in rat vascular smooth muscle cells
Li, Q. and S. Yokoyama (1995), J Biol Chem 270(44): 26216-23.
Abstract: Cholesterol was poorly available to free apolipoprotein (apo)A-I-mediated cellular lipid efflux from cholesterol-loaded rat vascular smooth muscle cells generating cholesterol-poorer pre-beta-HDL particles than those generated from macrophages by the same reaction (Li, Q., Komaba, A., and Yokoyama, S. (1993) Biochemistry 32, 4597-4603). The factors known to induce transformation of the smooth muscle cells into a macrophage-like stage were used in order to modulate this reaction, such as human platelet-derived growth factor, macrophage colony-stimulating factor, and phorbol 12-myristate-13-acetate (PMA). When the cells were stimulated by PMA following the pretreatment with platelet-derived growth factor plus macrophage colony-stimulating factor, cholesterol efflux mediated by free apoA-I increased 3-fold without changing phospholipid efflux, resulting in generation of pre-beta-HDL particles more rich in cholesterol. This treatment had only a little or no effect on apparent cellular cholesterol efflux to HDL or lipid microemulsion, respectively. Overall cellular free cholesterol pool size was unaffected by the treatment, and probing by extracellular cholesterol oxidase did not detect gross change in the cellular surface cholesterol. This specific enrichment of cholesterol in the apoA-I-mediated cellular lipid efflux was reversed by protein kinase C inhibitors. Measurement of intracellular cholesterol esterification suggested that PMA induced translocation of intracellular cholesterol to a specific pool for apoA-I-mediated efflux, and a protein kinase C inhibitor reversed this effect.

Indication of treatments based on extracorporeal elimination of cholesterol
Teruel, J. L. and M. A. Lasuncion (1992), Med Clin (Barc) 99(11): 417-9.

Indications for cholesterol-lowering medication: comparison of risk-assessment methods
Durrington, P. N., H. Prais, et al. (1999), Lancet 353(9149): 278-81.
Abstract: BACKGROUND: Recommendations for the prescription of lipid-lowering drugs emphasise the importance of an assessment of absolute coronary heart disease (CHD) risk based on all risk factors, rather than simply the serum cholesterol concentration. If, however, the methods recommended for risk assessment are inaccurate, recommended prescribing will not occur. We compared several sets of guidelines for such treatment in a series of patients referred to a lipid clinic, to assess the difference in degree of risk of CHD at which lipid-lowering medication is recommended by each set of guidelines. METHODS: For a series of 570 patients (50% men) without pre-existing clinical evidence of atherosclerosis referred to a lipid clinic, we compared the algorithms, charts, and tables used by the US National Cholesterol Education Program (NCEP), the joint guidelines of the European Society of Cardiology, the European Atherosclerosis Society, and the European Society of Hypertension, and the report of the UK Standing Medical Advisory Committee with the Framingham risk equation programmed into a computer. FINDINGS: In 386 patients for whom the NCEP and UK guidelines could be compared, 62% of the men and 72% of the women met NCEP criteria for lipid-lowering medication, whereas only 9% of the men and less than 1% of the women met the UK criteria. The Framingham equation estimated a CHD risk of more than 3% per year in 22% of the men and 7% of the women, which shows that the UK tables underestimated CHD risk. European guidelines could be applied to only 261 patients, and were reasonably accurate in assessment of a CHD risk of 2% per year. INTERPRETATION: Guidelines for the use of statin treatment in patients with CHD differ in their assessment of CHD risk. The method of risk assessment recommended in future guidelines for CHD prevention should be critically tested in relevant groups of patients.

Indicators of atherosclerosis risk. Evaluation with coronary angiography in non diabetic men with total cholesterol levels equal to or below 240 mg/dl
Arteaga, A., A. Martinez, et al. (1995), Rev Med Chil 123(2): 145-57.
Abstract: We studied 90 male non diabetic patients aged between 40 and 65 years old with a total cholesterol of less than 240 mg/dl and not receiving cholesterol reducing drugs, that were subjected to elective coronary arteriography. Weight, height, blood pressure and smoking habits were recorded and a fasting blood sample was drawn to measure total and HDL cholesterol, triglycerides, apoproteins A1 and B, Lipoprotein(a) and plasma cholesteryl ester transfer activity. Arteriography disclosed coronary lesions in 54 patients. Compared to patients without lesions, the former had lower HDL cholesterol (34 +/- 9.8 vs 40.2 +/- 11.6 mg/dl) and higher total cholesterol/HDL cholesterol and apoB/apoA1 ratios. No differences were found for lipoprotein(a) and plasma cholesteryl ester transfer activity. Univariate analysis showed that low HDL cholesterol had the best predictive capacity for atherosclerosis.

Indinavir alters sterol and fatty acid homeostatic mechanisms in primary rat hepatocytes by increasing levels of activated sterol regulatory element-binding proteins and decreasing cholesterol 7alpha-hydroxylase mRNA levels
Williams, K., Y. P. Rao, et al. (2004), Biochem Pharmacol 67(2): 255-67.
Abstract: Human immunodeficiency virus protease inhibitors induce hyperlipidemia in many patients treated with these drugs. We examined the effects of indinavir on cholesterol and bile acid homeostatic mechanisms in a primary rat hepatocyte (PRH) culture model. In PRH, indinavir up-regulated (2.5-fold) 3-hydroxy-3-methylglutaryl-Coenzyme A reductase mRNA levels 24hr after drug addition. In these same experiments, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels, the rate-limiting enzyme in bile acid biosynthesis, was decreased up to 10-fold. Fatty acid synthase mRNA levels were up-regulated more than 3-fold under these conditions. Indinavir did not alter CYP7A1 transcriptional activity, but decreased CYP7A1 mRNA half-life in PRH from 1.5hr to less than 0.5hr. Sterol regulatory element-binding protein-1 (SREBP-1) mature form was increased approximately 6-fold by this drug. Indinavir-induced mRNA changes and SREBP-1 mature protein levels were significantly abated by the addition of cholesterol, solubilized in beta-cyclodextrin, to culture medium. Indinavir markedly decreased endogenous cholesterol esterification and increased cholesterol in intracellular membranes in primary hepatocytes. Indinavir gavaged into intact mice also markedly increased SREBP-1 and SREBP-2 (mature forms) in hepatic nuclei. CYP7A1 mRNA was also decreased approximately 52% in indinavir-treated animals. We propose that indinavir disrupts cellular cholesterol homeostasis by increasing SREBP's and decreasing CYP7A1 mRNA.

Indirect evidence for hepatic induction in patients with cholesterol gallstones
Sandle, L. N., H. V. Worthington, et al. (1997), Biochem Soc Trans 25(3): 412S.

Individual cholesterol variation in response to a margarine- or butter-based diet: A study in families
Denke, M. A., B. Adams-Huet, et al. (2000), Jama 284(21): 2740-7.
Abstract: CONTEXT: The effectiveness of dietary modification in reducing low-density lipoprotein cholesterol (LDL-C) levels can be reliably predicted for populations, but not for individuals. OBJECTIVE: To determine whether individual variation in cholesterol response to dietary modification is a familial trait. DESIGN: Two-period, outpatient crossover trial conducted from September 1997 to September 1999. SETTING AND PARTICIPANTS: Fifty-six families from the Dallas-Ft Worth, Tex, area with 2 biological parents and at least 2 children aged 5 years or older volunteered; 46 families (n = 92 adults and n = 134 children) completed the study. INTERVENTION: All families followed two 5-week dietary regimens that included individualized daily dietary prescriptions and emphasized a low-saturated fat diet supplemented with specially manufactured baked goods and spreadable fat. One regimen used butter only and the other used margarine only. MAIN OUTCOME MEASURE: Mean LDL-C levels during the last 2 weeks of each dietary period. RESULTS: Margarine intake compared with butter intake lowered LDL-C levels 11% in adults (95% confidence interval CI, 13% to 9%) and 9% in children (95% CI, 12% to 6%) (P<.001 for both adults and children). The distribution of individual responses were peaked around the mean response. For adults and children together, family membership accounted for 19% of variability in response (P =.007). In children, family membership accounted for 40% of variability in response of percent change in LDL-C levels (P =.002). Body mass index and change in cholesterol ester (CE) 18:2/18:1 ratio accounted for 26% of variation, leaving 26% still attributable to family membership. In all participants, BMI predicted response-heavier individuals had higher LDL-C levels, less excursion in CE fatty acids, and less LDL-C response to dietary change. CONCLUSIONS: Our results suggest that individual variation in response to a cholesterol-lowering diet is a familial trait. Body weight is an important modifiable factor that influences response. JAMA. 2000;284:2740-2747.

Individual responses to a cholesterol-lowering diet in 50 men with moderate hypercholesterolemia
Denke, M. A. and S. M. Grundy (1994), Arch Intern Med 154(3): 317-25.
Abstract: BACKGROUND: Dietary modification is the recommended first step in the treatment of hypercholesterolemia. However, the efficacy of the National Cholesterol Education Program Step 1 Diet in outpatients with hypercholesterolemia has been debated. METHODS: Fifty normotriglyceridemic men whose ad libitum low-density lipoprotein (LDL) cholesterol levels were 4.14 to 5.69 mmol/L (160 to 220 mg/dL) participated in a two-period outpatient diet counseling study that used a 1-month high-fat, high-saturated fatty acid period (Hi-Sat) and a 4-month low-fat, low-saturated fatty acid period (Step 1 Diet). Lipid, lipoprotein levels, and plasma triglyceride fatty acids were measured five times during the last 2 weeks of each dietary period and averaged for each patient. Dietary intake was assessed by 7-day food records. During the Hi-Sat period, an LDL turnover study was done to determine the fractional catabolic rate of LDL. RESULTS: The mean reduction in total and LDL cholesterol levels achieved by diet was 0.54 mmol/L (21 mg/dL) and 0.39 mmol/L (15 mg/dL), respectively. These responses equaled those predicted from metabolic ward investigations. While dietary responsiveness was normally distributed, there was marked individual variation in response. The mean (+/- SD) for quartiles of LDL responsiveness were +0.41 +/- 0.21 mmol/L (+16 +/- 8 mg/dL), -0.16 +/- 0.13 mmol/L (-6 +/- 5 mg/dL), -0.57 +/- 0.16 mmol/L (-22 +/- 6 mg/dL), and -1.16 +/- 0.26 mmol/L (-45 +/- 10 mg/dL). These differences in response were partially explained by dietary adherence, baseline fractional catabolic rates of LDL, and the change in plasma triglyceride palmitate level. CONCLUSIONS: The Step 1 Diet is effective in lowering LDL cholesterol levels for many hypercholesterolemic men, and with appropriate counseling, outpatients can achieve results predicted by inpatient metabolic diet studies. Nonetheless, the responsiveness for individuals is highly variable, and this variability is influenced by both compliance and biologic factors. Since many men achieved LDL cholesterol levels low enough to remove the need for drug therapy in primary prevention for coronary heart disease, dietary therapy should remain the initial approach to the treatment of hypercholesterolemia.

Individual responsiveness to a cholesterol-lowering diet in postmenopausal women with moderate hypercholesterolemia
Denke, M. A. (1994), Arch Intern Med 154(17): 1977-82.
Abstract: BACKGROUND: The efficacy of the step 1 diet in outpatient women with hypercholesterolemia has been debated. METHODS: Forty-one normotriglyceridemic women whose low-density lipoprotein (LDL) cholesterol levels were 3.62 to 5.17 mmol/L (140 to 200 mg/dL) participated in a two-period outpatient diet counseling study that used a 1-month high-fat, high-saturated fatty acid period (Hi-Sat diet) and a 4-month low-fat, low-saturated fatty acid period (step 1 diet). All women were postmenopausal and were not taking hormone replacement therapy. Levels of lipids, lipoproteins, and plasma triglyceride fatty acids were measured five times during the last 2 weeks of each dietary period. Dietary intake was assessed by 7-day food records. RESULTS: The mean reduction in total cholesterol level achieved by the step 1 diet was 0.36 mmol/L (14 mg/dL). The reduction in total cholesterol level was seen in both LDL cholesterol levels (0.28 mmol/L 11 mg/dL; P <.005) and high-density lipoprotein cholesterol levels (0.08 mmol/L 3 mg/dL; P =.08). Although individual LDL responsiveness to diet was normally distributed, there was marked variation in response, which could be explained only partially by compliance (change in saturated fat intake, 10%), change in body weight (3%), and an interaction between the palmitic acid content of the plasma and body weight (3%). CONCLUSIONS: A step 1 diet lowers total and LDL cholesterol levels in postmenopausal women. A nonsignificant reduction in high-density lipoprotein cholesterol levels was also observed. Since some women achieved LDL cholesterol levels low enough to obviate the need for drug therapy as primary prevention of coronary heart disease, dietary therapy should remain the first step in the management of hypercholesterolemia in postmenopausal women.

Individual variability in lipoprotein cholesterol response to National Cholesterol Education Program Step 2 diets
Schaefer, E. J., S. Lamon-Fava, et al. (1997), Am J Clin Nutr 65(3): 823-30.
Abstract: The effects of National Cholesterol Education Program (NCEP) Step 2 diets on plasma lipoprotein profiles in 72 men mean (+/- SD) age: 44 +/- 15 y, range: 19-81 y and 48 women (mean age: 50 +/- 21 y, range: 21-78 y) participating in five previously published studies were examined. Subjects were placed on a baseline diet similar to an average American diet (35-41% total fat, 13-16% saturated fat, 31-45 mg cholesterol/MJ) and then on an NCEP Step 2 diet (18-29% total fat, 4-7% saturated fat, 11-20 mg cholesterol/MJ) under isoenergetic conditions. All food and drink were provided. Compared with the baseline diet, consumption of the NCEP Step 2 diets was associated with significant decreases in concentrations of low-density-lipoprotein (LDL) cholesterol (-18.9% and -15.6%, respectively) and high-density-lipoprotein (HDL) cholesterol (-17.0% and -11.2%, respectively) in both men and women. Men with the apolipoprotein (apo) E 3,4 phenotype had a significantly greater decrease in LDL cholesterol (-24.2%) with the NCEP Step 2 diets than men with the apo E 3,3 phenotype (-17.7%). Men with the apo A-IV 1,2 phenotype tended to have less LDL cholesterol lowering (-12.8%) than men with the apo A-IV 1,1 phenotype (-19.6%), but this difference was not significant. No differences were seen by apo E and A-IV phenotype in women. A large variability in lipid response to the diet was observed, with changes in LDL cholesterol ranging from +3% to -55% in men and and from +13% to -39% in women. Forty-eight percent of the variability in LDL-cholesterol response (in mmol/L) to the diet could be accounted for by baseline LDL concentrations and age in men, and 13% by age in women.

Individual variation in plasma cholesterol response to dietary saturated fat
Cox, C., J. Mann, et al. (1995), Bmj 311(7015): 1260-4.
Abstract: OBJECTIVE--To determine the extent to which plasma lipid concentrations of individuals are consistently sensitive to changes in saturated fats; to examine whether groups that consistently have large or small responses can be defined; and to identify factors which predict response of lipids to dietary change. DESIGN--A double crossover design in which two diets (S, providing 21% energy from saturated fat, and P, providing 10%) were followed for periods of six weeks in the sequence SPSP or PSPS. SETTING--67 free living subjects, total cholesterol 5.5-7.9 mmol/l. MAIN OUTCOME MEASURES--Relation of cholesterol responses to repeated dietary changes and of potential predictors and cholesterol response. RESULTS--Similar average changes in cholesterol mask a wide range of individual responses. Response was not related to compliance. In all participants the change in cholesterol observed when the nature of dietary fat was changed on the two crossovers was correlated (r = 0.31, P = 0.01); the degree of correlation between the two sets of responses was greater in the 46 consistent responders than in the 21 variable responders (r = 0.71 v r = 0.21). Mean differences in cholesterol between diet S and diet P during the two crossovers were 1.16 (SD 0.35) mmol/l and 0.95 (0.26) mmol/l for consistent hyperresponders and 0.18 (0.26) mmol/l and 0.18 (0.25) mmol/l for consistent minimal responders. In consistent responders, changes in total cholesterol in response to increasing saturated fats correlated with baseline cholesteryl ester transfer activity (r = 0.32, P = 0.03); total cholesterol (r = 0.37, P = 0.01); triglycerides (r = 0.30, P = 0.04); and apolipoprotein B (r = 0.54, P = 0.01). CONCLUSIONS--There is a degree of consistency in cholesterol response to instructions to change dietary fat which is not explained by dietary compliance, and there are groups of consistent hyperresponders and minimal responders within a population of hypercholesterolaemic individuals. Several factors predicting response have been identified. These results have relevance to dietary approaches aimed at reducing the lipoprotein mediated risk of coronary heart disease.

Individualized dietary counselling of families: serum cholesterol concentration and growth of children aged 7-13 months
Lapinleimu, H., E. Jokinen, et al. (1994), Acta Paediatr 83(4): 383-8.
Abstract: We studied the effect of a change in dietary fat composition on serum total and high-density lipoprotein cholesterol and growth in healthy infants between 7 and 13 months of age. The intervention families (n = 22) received individualized dietary counselling when the infant was 7, 8 and 10 months of age. The intervention diet was designed to have a fat content of 35-45 E% of total energy intake in infants aged 7-12 months and 30-35 E% after 12 months of age. The ratio of saturated to monounsaturated to polyunsaturated fatty acids was designed to be 1:1:1. The children in the control group (n = 23) were given no specific advice on the fat composition of the diet. Intake of polyunsaturated fatty acids was significantly higher in the intervention group than in the controls (5.9 E% versus 3.6 E%, p < 0.05). Serum total cholesterol concentration decreased significantly in the intervention group during the study from 4.16 +/- 0.41 mmol/l to 3.86 +/- 0.48 mmol/l (p < 0.05). The infants of both groups grew like average Finnish children. Modification of dietary fat composition, as widely recommended for adults and older children to prevent coronary heart disease, decreases cholesterol values in infants without affecting their normal growth.

Individuals with high total cholesterol/HDL cholesterol ratios are insulin resistant
Jeppesen, J., F. S. Facchini, et al. (1998), J Intern Med 243(4): 293-8.
Abstract: OBJECTIVES: To define the pathophysiologic characteristics of patients at high risk for coronary heart disease due to an increased ratio of total cholesterol (TC) to high density lipoprotein-cholesterol (HDL-C). DESIGN: Cross-sectional. SETTING: Clinical Research Center. SUBJECTS: One hundred-20 healthy, non-diabetic, normotensive, volunteers were screened for this study. From this pool, 40 individuals (20 females and 20 males) with the highest and the lowest TC/HDL-C ratios were selected for comparison. MAIN OUTCOME MEASURES: Values for body mass index (BMI), ratio of waist to hip girth (WHR), and blood pressure were obtained on all patients. In addition, measurements were made of fasting lipid and lipoprotein concentrations, plasma glucose and insulin responses to an oral glucose challenge, and insulin resistance as assessed by the insulin suppression test. RESULTS: Age, BMI, and WHR were the same in the two groups. However, the group with a high TC/HDL-C ratio had higher (P < 0.05) systolic and diastolic blood pressures. In addition, patients with a high TC/HDL-C ratio had significantly higher (P < 0.001) very low density (VLDL) and low density lipoprotein (LDL)-cholesterol concentrations and lower HDL-cholesterol concentrations, with significant (P < 0.001) correlations between the TC/HDL-C ratio and VLDL (r = 0.60), LDL (r = 0.54), and HDL (r = -0.73) cholesterol concentrations. Patients with a high TC/HDL-C ratio were also significantly (P < 0.05-0.001) more insulin resistant, glucose intolerant with a greater plasma insulin response to oral glucose, and hypertriglyceridemic. CONCLUSIONS: The results indicate that an increase in LDL-cholesterol concentration is not necessarily the major contributor to a high ratio of TC/HDL-C. Furthermore, individuals with this epidemiologic designation are insulin resistant, and liable to all the other abnormalities associated with this metabolic defect.

Indomethacin decreases viscosity of gallbladder bile in patients with cholesterol gallstone disease
von Ritter, C., A. Niemeyer, et al. (1993), Clin Investig 71(11): 928-32.
Abstract: There is experimental evidence that inhibition of cyclooxygenase with nonsteroidal anti-inflammatory drugs may decrease cholesterol gallstone formation and mitigate biliary pain in gallstone patients. The mechanisms by which NSAIDs exert these effect are unclear. In a prospective, controlled clinical trial we examined the effects of oral indomethacin on the composition of human gallbladder bile. The study included 28 patients with symptomatic cholesterol or mixed gallstones. Of these, 8 were treated with 3 x 25 mg indomethacin daily for 7 days prior to elective cholecystectomy while 20 received no treatment and served as controls. Bile and tissue samples from the gallbladder were obtained during cholecystectomy. Indomethacin tissue levels in the gallbladder mucosa, as assessed by HPLC, were 1.05 +/- 0.4 ng/mg wet weight, a concentration known to inhibit effectively cyclooxygenase activity. Nevertheless, no differences between the treated and untreated groups were found in the concentrations of biliary mucus glycoprotein (0.94 +/- 0.27 versus 0.93 +/- 0.32 mg/ml) or total protein (5.8 +/- 0.9 versus 6.4 +/- 1.3 mg/ml), cholesterol saturation (1.3 +/- 0.2 versus 1.5 +/- 0.2), or nucleation time (2.0 +/- 3.0 versus 1.5 +/- 2.0 days). However, biliary viscosity, measured using a low-shear rotation viscosimeter, was significantly lower in patients receiving indomethacin treatment (2.9 +/- 0.6 versus 5.6 +/- 1.2 mPa.s; P < 0.02). In conclusion, in man oral indomethacin decreases bile viscosity without alteration of bile lithogenicity or biliary mucus glycoprotein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Induced mutant mice expressing lipoprotein lipase exclusively in muscle have subnormal triglycerides yet reduced high density lipoprotein cholesterol levels in plasma
Levak-Frank, S., P. H. Weinstock, et al. (1997), J Biol Chem 272(27): 17182-90.
Abstract: To determine the contribution of muscle lipoprotein lipase (LPL) to lipoprotein metabolism, induced mutant mice were generated that express human LPL exclusively in muscle. By cross-breeding heterozygous LPL knockout mice with transgenic mice expressing human LPL only in muscle, animals were obtained that express human LPL primarily in skeletal muscle on either the null (L0-MCK) or normal (L2-MCK) LPL backgrounds, and these were compared with control littermates (L2). Fed and fasted post-heparin plasma (PHP) LPL activities were increased 1.4- and 2.3-fold, respectively, in L2-MCK mice and were normal in L0-MCK mice compared with controls. The specific enzyme activities of human LPL in mouse plasma was comparable to human LPL in human PHP. Skeletal muscle LPL activity was increased in both L2-MCK and L0-MCK mice in the fed (6.6-fold) and fasted (4.2-fold in L2-MCK; and 3.4-fold in L0-MCK) states. Adipose tissue LPL mRNA and activity were not detectable in L0-MCK mice. Growth and body mass composition were similar among all groups. In the fasted and fed state, L2-MCK mice had 31% and 53% reductions, respectively, in plasma triglycerides (TG), compatible with increased PHP LPL activity. Unexpectedly, both in the fasted and fed state the L0-MCK mice also had reduced TG (22%), despite normal PHP LPL activities. Very low density lipoprotein (VLDL) turnover studies revealed that the decreased TG were due to increased particle fractional catabolic rate in both L2-MCK and L0-MCK mice. Despite reduced TG, both L2-MCK and L0-MCK mice showed reduced high density lipoprotein (HDL) cholesterol levels (16% and 19%, respectively). HDL turnover studies indicated increased HDL cholesteryl ester fractional catabolic rate in the L2-MCK and L0-MCK compared with control mice. In summary, these studies suggest that muscle LPL is particularly potent with regard to VLDL metabolism and is sufficient to compensate for the lack of LPL in other tissues with regard to lipolyzing VLDL particles. With regard to HDL, muscle LPL expression does not result in normal levels due to enhanced breakdown either by mediating accelerated HDL clearance or by failing to establish normal HDL particles that are then cleared more quickly than normal. These studies provide new insights on the tissue-specific effects of LPL on lipoprotein metabolism.

Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels
Levak-Frank, S., W. Hofmann, et al. (1999), Proc Natl Acad Sci U S A 96(6): 3165-70.
Abstract: The tissue-specific expression of lipoprotein lipase (LPL) in adipose tissue (AT), skeletal muscle (SM), and cardiac muscle (CM) is rate-limiting for the uptake of triglyceride (TG)-derived free fatty acids and decisive in the regulation of energy balance and lipoprotein metabolism. To investigate the tissue-specific metabolic effects of LPL, three independent transgenic mouse lines were established that expressed a human LPL (hLPL) minigene predominantly in CM. Through cross-breeding with heterozygous LPL knockout mice, animals were generated that produced hLPL mRNA and enzyme activity in CM but lacked the enzyme in SM and AT because of the absence of the endogenous mouse LPL gene (L0-hLPL). LPL activity in CM and postheparin plasma of L0-hLPL mice was reduced by 34% and 60%, respectively, compared with control mice. This reduced LPL expression was sufficient to rescue LPL knockout mice from neonatal death. L0-hLPL animals developed normally with regard to body weight and body-mass composition. Plasma TG levels in L0-hLPL animals were increased up to 10-fold during the suckling period but normalized after weaning and decreased in adult animals. L0-hLPL mice had normal plasma high-density lipoprotein (HDL)-cholesterol levels, indicating that LPL expression in CM alone was sufficient to allow for normal HDL production. The absence of LPL in SM and AT did not cause detectable morphological or histopathological changes in these tissues. However, the lipid composition in AT and SM exhibited a marked decrease in polyunsaturated fatty acids. From this genetic model of LPL deficiency in SM and AT, it can be concluded that CM-specific LPL expression is a major determinant in the regulation of plasma TG and HDL-cholesterol levels.

Inducing cholesterol precipitation from pig bile with beta-cyclodextrin and cholesterol dietary supplementation
Juste, C., I. Catala, et al. (1997), J Hepatol 26(3): 711-21.
Abstract: BACKGROUND/METHODS: In this study, pigs fed for 3 weeks a well-balanced semi-purified diet enriched with 0.3% cholesterol and 0, 5 or 10% beta-cyclodextrin were proposed as new animal donors of gallbladder bile exhibiting different rates of cholesterol crystallization, in order to gain insight into the early mechanisms underlying cholesterol precipitation in vivo. The appearance and growth of cholesterol crystals were monitored in the incubated freshly collected gallbladder biles through light microscopy and concomitant time-sequential determination of crystallized cholesterol concentration, and interpreted in terms of the composition of the bile. RESULTS: Although the concentration of total lipids and proteins and the relative proportions of bile acids, phospholipids, and cholesterol remained unchanged under beta-cyclodextrin, the cholesterol crystallization increased in the following order: 0<<10<5% beta-cyclodextrin. Concomitantly, the proportion of chenodeoxycholic acid in bile, and the hydrophobicity index of the biliary bile acid mixture increased in the following order: 0<5<10% beta-cyclodextrin (the same as reported elsewhere for the decrease in the antinucleating ApoA1), while sn-2 arachidonoyl biliary lecithins were specifically increased with 5% beta-cyclodextrin in the diet. CONCLUSIONS: We hypothesized that lecithin molecular species may be the determinant factor in modulating high cholesterol crystallization rates in biles otherwise enriched with hydrophobic bile acids.

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