Cholesterol Journal Articles

Record 921 to 940

Apolipoprotein E and complement C3 polymorphism and their role in the response to gemfibrozil and low fat low cholesterol therapy
Nemeth, A., K. Szakmary, et al. (1995), Eur J Clin Chem Clin Biochem 33(11): 799-804.
Abstract: Three different allelic variants of apolipoprotein E determine, in concert with other gene products, the levels of plasma lipoproteins. Recently, cleavage products of the complement C3 molecule have also been implicated in determining plasma triacylglycerol concentrations. This study presents data of an ongoing study to dissect the role of the apolipoprotein E gene locus in the response to low fat/low cholesterol diet combined with gemfibrozil treatment. In addition, for the first time, the significance of C3 allelic variants to such hypolipidaemic therapy response was analysed. To this end data from 81 obese hyperlipoproteinaemic patients (Fredrickson type II/A and B and type IV and V) confirmed the usefulness of the combined gemfibrozil/diet treatment and unveiled apolipoprotein E allele group specific therapy responses. The mean changes of lipid properties due to combined treatment was 15% for total cholesterol, 48% for triacylglycerols and 28% for atherogenic index. Division into hyperlipidaemia types according to Fredrickson and subgrouping into E2, E3 and E4 groups (apolipoprotein E2/2 and 2/3, apolipoprotein E3/3 and apolipoprotein E4/2 and 4/3 phenotype groups respectively) exposed pronounced differences from these mean changes, suggesting substantial influence of apolipoprotein E variants on this therapy. We observed triacylglycerol reductions of from 17% in type IIA-apolipoprotein E3 group patients up to 78% in the type IV and V-apolipoprotein E2 group. Thus it might be concluded the apolipoprotein E genotyping aides therapy success prediction. Although, low sample number in some subgroups obscures significance in this pilot study, significant therapy success emerges for the E3 and E4 group in type IV and V hyperlipidaemia and type IIB-apolipoprotein E3 homozygous patients can be predicted to respond better than apolipoprotein E2 carriers. Finally, we present evidence that positive changes of lipid properties are also determined by the "fast" complement C3 allel (C3-F). Patients with complement factor C3-FS pattern respond better to treatment than patients with C3-SS configuration. In summary these data endorse the genotyping of apolipoprotein E alleles to predict maximal success of "fibrate" treatment. In addition they argue strongly for further assessment of the involvement of complement C3 allelic variations in lipid homeostasis.

Apolipoprotein E competitively inhibits receptor-dependent low density lipoprotein uptake by the liver but has no effect on cholesterol absorption or synthesis in the mouse
Woollett, L. A., Y. Osono, et al. (1995), Proc Natl Acad Sci U S A 92(26): 12500-4.
Abstract: This study examines the question of whether apolipoprotein E (apoE) alters steady-state concentrations of plasma cholesterol carried in low density lipoproteins (LDL-C) by acting as a competitive inhibitor of hepatic LDL uptake or by altering the rate of net cholesterol delivery from the intestinal lumen to the liver. To differentiate between these two possibilities, rates of cholesterol absorption and synthesis and the kinetics of hepatic LDL-C transport were measured in vivo in mice with either normal (apoE+/+) or zero (apoE-/-) levels of circulating apoE. Rates of cholesterol absorption were essentially identical in both genotypes and equaled approximately 44% of the daily dietary load of cholesterol. This finding was consistent with the further observation that the rates of cholesterol synthesis in the liver (approximately 2,000 nmol/h) and extrahepatic tissues (approximately 3,000 nmol/h) were also essentially identical in the two groups of mice. However, the apparent Michaelis constant for receptor-dependent hepatic LDL-C uptake was markedly lower in the apoE-/- mice (44 +/- 4 mg/dl) than in the apoE+/+ animals (329 +/- 77 mg/dl) even though the maximal transport velocity for this uptake process was essentially the same (approximately 400 micrograms/h per g) in the two groups of mice. These studies, therefore, demonstrate that apoE-containing lipoproteins can act as potent competitive inhibitors of hepatic LDL-C transport and so can significantly increase steady-state plasma LDL-C levels. This apolipoprotein plays no role, however, in the regulation of cholesterol absorption, sterol biosynthesis, or hepatic LDL receptor number, at least in the mouse.

Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease
Kivipelto, M., E. L. Helkala, et al. (2002), Ann Intern Med 137(3): 149-55.
Abstract: BACKGROUND: Presence of the apolipoprotein E (apoE) epsilon4 allele, which is involved in cholesterol metabolism, is the most important genetic risk factor for Alzheimer disease. Elevated midlife values for total cholesterol level and blood pressure have been implicated recently as risk factors for Alzheimer disease. OBJECTIVE: To study the relative importance and the putative relationship among the apoE epsilon4 allele, midlife total cholesterol level, and midlife blood pressure as risk factors for late-life Alzheimer disease. DESIGN: Prospective population-based study. SETTING: Kuopio and Joensuu, eastern Finland. PARTICIPANTS: Participants were derived from random population surveys from 1972, 1977, 1982, and 1987. A total of 1449 persons (73%), 65 to 79 years of age, participated in the reexamination in 1998 (mean follow-up, 21 years). MEASUREMENTS: Midlife blood pressure and total cholesterol level, apoE genotype, and development of Alzheimer disease during follow-up. RESULTS: The apoE epsilon4 allele was an independent risk factor for Alzheimer disease, even after adjustment for midlife vascular risk factors and other confounders (odds ratio, 2.1 95% CI, 1.1 to 4.1). Similarly, elevated midlife values for serum total cholesterol level (odds ratio, 2.8 CI, 1.2 to 6.7) and systolic blood pressure (odds ratio, 2.6 CI, 1.1 to 6.6) were independent risk factors for Alzheimer disease, even after adjustment for apoE genotype and other confounding factors. CONCLUSIONS: The association between the apoE epsilon4 allele and Alzheimer disease does not seem to be mediated by vascular factors. The apoE epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for Alzheimer disease. The risk for Alzheimer disease from treatable factors--elevated total cholesterol level and blood pressure--appears to be greater than that from the apoE epsilon4 allele.

Apolipoprotein E expression by human-monocyte-derived macrophages. Modulation by opsonised zymosan and cholesterol
Rouis, M., F. Nigon, et al. (1990), Eur J Biochem 189(2): 447-53.
Abstract: The effects of opsonised zymosan and of acetylated low-density lipoprotein (AcLDL) on the synthesis and secretion of apolipoprotein E (apoE), and of apoE mRNA abundance, have been studied in human-monocyte-derived macrophages (MDM). Stimulation by opsonised zymosan led to a concentration-dependent increase in apoE secretion; non-opsonised zymosan was without effect. Incubation with AcLDL led to a concentration-dependent elevation in apoE synthesis which paralleled the increase in cellular cholesterol content. The opsonised-zymosan-induced stimulation of apoE production was additive to that resulting from cholesterol loading with AcLDL. Opsonised zymosan alone did not affect the cholesterol content of MDM. Cholesterol-loaded MDM remained responsive to opsonised zymosan stimulation, displaying a 3.5-fold elevation in apoE secretion as compared to their non-stimulated counterparts. Cell-associated apoE remained at trace levels under all conditions of cell treatment. Studies involving 35Smethionine incorporation showed de novo synthesis of apoE to be enhanced in both cholesterol-loaded and opsonised-zymosan-stimulated macrophages. Estimation of apoE mRNA in opsonised-zymosan-stimulated and control MDM by dot-blot analysis revealed similar message abundance; by contrast, elevation in cellular cholesterol content following incubation with modified LDL led to a significant increase in apoE mRNA levels. We conclude that the opsonised-zymosan-induced stimulation of apoE synthesis and secretion in human MDM may occur by a mechanism(s) independent of cellular cholesterol content.

Apolipoprotein E expression in Y1 adrenal cells is associated with increased intracellular cholesterol content and reduced free cholesterol efflux
Prack, M. M., G. H. Rothblat, et al. (1994), Biochemistry 33(17): 5049-55.
Abstract: The expression of apoE mRNA in the adrenal gland is inversely correlated to steroidogenesis and directly correlated to the level of cholesteryl ester stores. To further investigate the relationship between apoE and cellular cholesterol homeostasis, several parameters of cholesterol metabolism in the murine Y1 adrenal cell line engineered to constitutively express human apoE (Y1-E cells) have been studied. It is reported here that Y1-E cells have increased cellular cholesterol content and markedly reduced efflux of free cholesterol as compared to control Y1 cells that do not express apoE. Y1-E cells have increases in both free and esterified cholesterol. However, Y1 and Y1-E cells incorporate 14Coleate into cholesteryl ester at similar rates and have similar levels of maximal ACAT activity in isolated microsomes. Turnover of cholesteryl ester stores prelabeled with 14Coleate occurred at similar rates in Y1-E and control Y1 cells, suggesting that increased cholesteryl ester stores in Y1-E cells do not result from reduced cholesteryl ester hydrolysis. Y1-E cells showed reduced cholesterol efflux as compared to control Y1 cells with either native high-density lipoprotein or cholesterol-free reconstituted particles as extracellular acceptors. Cholesterol efflux was not altered by inhibition of ACAT, suggesting that cholesterol esterification in Y1-E cells is not inhibiting efflux. These results suggest that reduced cholesterol efflux is responsible, at least in part, for the cholesterol accumulation in Y1-E cells. In comparison to the rat adrenal gland in vivo, Y1-E cells resemble adrenocortical cells under conditions where steroidogenesis is suppressed and apoE expression and cholesteryl ester storage are increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein E gene polymorphisms and serum cholesterol in healthy Irish adults: a proposed genetic marker for coronary artery disease risk
Sheehan, D., T. Bennett, et al. (2000), Ir J Med Sci 169(1): 50-4.
Abstract: BACKGROUND: The apolipoprotein (Apo) E gene, and thus its gene product, plays a central and pervasive role in lipid metabolism by serving as a ligand for lipoprotein receptors. Polymorphisms of this gene have been associated with variation in lipid phenotypes in some Caucasian and Asian populations, but not in others. No such study has been carried out in a resident Irish population. AIM: A study was designed to examine the relationship between serum cholesterols and Apo E genotype in a cohort of healthy Irish adults. METHODS: One hundred healthy Irish adults, aged 19-65 years, were recruited from the Cork City area. Two fasting blood samples were collected from each subject. One was assayed for serum cholesterols--total and low-density lipoprotein (LDL), and high-density lipoprotein (HDL)--while the other sample was used for isolation of genomic DNA and determination of Apo E genotype. RESULTS: While the E2 (12%) was the least prevalent, E3 was the most prevalent Apo E genotype (66%) in this group of healthy Irish adults. A significant Apo E gene-dosage effect was evident, whereby individuals with the Apo E2 genotype had a lower level of total cholesterol, E3 had intermediate levels, and E4 had a higher level. Moreover, those with the Apo E4 genotype had a significantly higher level of LDL cholesterol compared to E2 or E3 genotypes. There was no significant difference in mean serum adjusted HDL-cholesterol levels between the three Apo E genotypes. CONCLUSION: These findings suggest that healthy Irish adults with the Apo E4 genotype have higher serum total and LDL-cholesterol levels than those with E2 or E3 Apo E genotypes and therefore may have a higher risk of atherosclerotic coronary artery disease and coronary heart disease in later life.

Apolipoprotein E gene promoter -219G->T polymorphism increases LDL-cholesterol concentrations and susceptibility to oxidation in response to a diet rich in saturated fat
Moreno, J. A., F. Perez-Jimenez, et al. (2004), Am J Clin Nutr 80(5): 1404-9.
Abstract: BACKGROUND: The apolipoprotein E (APOE) gene promoter polymorphism (-219G-->T) has been associated with increased risk of myocardial infarction, premature coronary artery disease, and decreased plasma apolipoprotein E concentrations. OBJECTIVE: We aimed to determine in healthy subjects whether this polymorphism modifies the susceptibility of LDL to oxidation and the lipid response to the content and quality of dietary fat. DESIGN: Fifty-five healthy men with the APOE3/E3 genotype (7 GG, 38 GT, and 10 TT) completed 3 dietary periods, each lasting 4 wk. The first was a saturated fatty acid (SFA)-rich diet 38% fat-20% SFA and 12% monounsaturated fatty acid (MUFA)-and 47% carbohydrates (CHO), which was followed by a CHO-rich diet (30% fat-<10% SFA and 12% MUFA-and 55% CHO) or a MUFA-rich diet (38% fat-<10% SFA and 22% MUFA-and 47% CHO) in a randomized crossover design. At the end of each dietary period, LDL oxidation susceptibility, lipids, and lipoproteins were measured. RESULTS: Compared with carriers of the G allele, TT subjects had a significantly (P < 0.05) shorter lag time after the SFA diet. The replacement of the SFA diet by the CHO or MUFA diet induced a greater increase (P < 0.05) in lag time in the TT subjects than in the GG or GT subjects. Carriers of the T allele had higher LDL-cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) plasma concentrations after the SFA diet than did GG subjects. Compared with GG subjects, carriers of the T allele had a significantly (P < 0.05) greater decrease in LDL cholesterol and apolipoprotein B when they changed from the SFA to the CHO diet. CONCLUSION: The -219G-->T polymorphism may partially explain differences in individual responses to diet.

Apolipoprotein E genotype and exercise training-induced increases in plasma high-density lipoprotein (HDL)- and HDL2-cholesterol levels in overweight men
Hagberg, J. M., R. E. Ferrell, et al. (1999), Metabolism 48(8): 943-5.
Abstract: We determined if the apolipoprotein E (APO E) genotype affects the exercise training-induced increase in plasma high-density lipoprotein cholesterol (HDL-C) and HDL2-C. Sedentary overweight men on an American Heart Association (AHA) step I diet had plasma lipoprotein-lipids measured before and after 9 months of endurance exercise training. APO E2 (n = 6), E3 (n = 33), and E4 (n = 12) groups were similar at baseline in terms of age, body weight and composition, and plasma lipoprotein-lipid profiles. APO E2 men had a larger increase in plasma HDL-C and HDL2-C with exercise training than APO E3 and E4 men (HDL-C, 8 +/- 4 v 3 +/- 1 v 2 +/- 1 mg/dL; HDL2-C, 5 +/- 3 v 1 +/- 1 v -1 +/- 1 mg/dL; mean +/- SE, all P <.01). After adjusting for body weight changes, the increases in plasma HDL-C and HDL2-C remained greater in APO E2 versus E3 and E4 men (all P <.03). These results indicate that APO E2 men may have greater plasma HDL-C and HDL2-C increases with endurance exercise training.

Apolipoprotein E genotype is a determinant of low-density lipoprotein cholesterol and of its response to a low-cholesterol diet in Type 1 diabetic patients with elevated urinary albumin excretion
Blaauwwiekel, E. E., B. J. Beusekamp, et al. (1998), Diabet Med 15(12): 1031-5.
Abstract: The effect of the apolipoprotein (apo) E genotype on the lipoprotein response to a 1 year low cholesterol diet (200 mg cholesterol per day) was evaluated in 36 patients with Type 1 diabetes mellitus with albuminuria between 10 and 200 microg min(-1). Apo E genotype was characterized by polymerase chain reaction and restriction isotyping. In 11 IDDM patients with at least one epsilon4 allele (apo E4 group), baseline serum total and low density lipoprotein (LDL) cholesterol were higher (p < 0.05 for both) than in 25 patients without an epsilon4 allele and with at least one epsilon3 allele (apo E3 group). Dietary counselling resulted in a similar decrease in cholesterol intake in both groups, whereas linoleic acid did not change. In the apo E4 group, serum total and LDL cholesterol at follow-up fell (p < 0.01 for both) to levels that were not different from those in the apo E3 group, and the changes in these parameters were greater (p < 0.02) than those in the apo E3 group. We conclude that the apo E4 allele is associated with atherogenic lipoprotein abnormalities in Type 1 DM patients with minor elevations in albuminuria when they use their habitual diet. Apo E4 carrying patients respond better to a low cholesterol diet.

Apolipoprotein E isoforms, serum cholesterol, and cancer. 1986
Katan, M. B. (2004), Int J Epidemiol 33(1): 9.

Apolipoprotein E phenotype regulates cholesterol absorption in healthy 13-month-old children--The STRIP Study
Tammi, A., T. Ronnemaa, et al. (2001), Pediatr Res 50(6): 688-91.
Abstract: High serum cholesterol concentration is one of the key risk factors in development of atherosclerosis, which may begin early in life and later progress to symptomatic coronary heart disease. In adults, apoE polymorphism strongly influences cholesterol metabolism, as subjects with apoE 3/4 or 4/4 (collectively called apoE4) phenotype absorb cholesterol effectively and thus also have higher cholesterol absorption-reflecting plant sterol concentrations in serum than subjects with other apoE phenotypes. Because of the inverse correlation of absorption and synthesis of cholesterol, concentrations of cholesterol synthesis-reflecting serum cholesterol precursor sterols are lower in subjects with apoE4 than in subjects with other phenotypes. To analyze whether apoE phenotype affects cholesterol absorption and synthesis in early childhood, we measured serum plant sterol (campesterol and sitosterol) and cholesterol precursor sterol (desmosterol and lathosterol) concentrations in healthy 13-month old children using gas-liquid chromatography. The 36 study children were participants in a randomized prospective trial (the Special Turku Coronary Risk Factor Intervention Project) aimed at decreasing exposure of the children to environmental atherosclerosis risk factors. The 16 apoE4 children had 30% to 50% higher cholesterol-adjusted campesterol and sitosterol concentrations in serum than the 20 apoE 3/3 children (p = 0.002 and p = 0.02, respectively). The concentrations of cholesterol precursor sterols in serum did not differ between the two groups of children. We conclude that the young apoE4 children may absorb cholesterol and plant sterols more effectively than the children with apoE 3/3 phenotype without compensatory reduction in endogenous synthesis of cholesterol.

Apolipoprotein E phenotype, cholesterol and breast and prostate cancer
Niemi, M., K. Kervinen, et al. (2000), J Epidemiol Community Health 54(12): 938-9.

Apolipoprotein E polymorphism and dietary plasma cholesterol response
Tikkanen, M., J. K. Huttunen, et al. (1995), Can J Cardiol 11 Suppl G: 93G-96G.
Abstract: All studies have demonstrated a strong association between plasma cholesterol and apoE phenotypes in the following order: E4/E4 > E4/E3 > E3/E3 > E3/E2. It has been thought possible that the apoE gene might be involved in the modulation of dietary plasma cholesterol responses, perhaps explaining the differences in cholesterol concentrations. Some dietary intervention studies have suggested that apoE4 individuals react to dietary change with exaggerated cholesterol responses. In one study, apoE4/E4 individuals responded by increased cholesterol reductions during low fat intake, and by increased cholesterol elevations during switchback to high fat diet. Plausible mechanisms have been postulated which could explain such differences. However, other studies have reported no differences in plasma lipid responses among apoE phenotypes. The studies cannot be directly compared because of different designs and study populations with differing apoE allele frequencies. Thus the possible role of genetic variation in the apoE gene in the modulation of dietary plasma lipid responses remains to be confirmed in prospective dietary studies, involving diets both rich and poor in fat and cholesterol.

Apolipoprotein E polymorphism and plasma cholesterol response to dietary change
Tikkanen, M. J. (1997), World Rev Nutr Diet 80: 15-21.

Apolipoprotein E polymorphism and serum cholesterol levels in Finnish children and adolescents
Lehtimaki, T., T. Moilanen, et al. (1994), Duodecim 110(14): 1313-9.

Apolipoprotein E polymorphism and serum lipids in a randomized, prospective trial of an infant diet with reduced saturated fat and cholesterol
Lapinleimu, H., J. Viikari, et al. (1996), Pediatrics 98(4 Pt 1): 757-62.
Abstract: BACKGROUND: The inherited apolipoprotein E (apoE) phenotype may determine effectiveness of dietary atherosclerosis prevention. This study analyzes the effects of apoE phenotypes on changes in serum lipid concentrations in a 6-month prospective, randomized trial of a low-saturated-fat, low-cholesterol diet in infancy. PATIENTS AND METHODS: One thousand sixty-two healthy infants were randomized to intervention and control groups at the age of 7 months. Counseling was provided to the intervention families when the children's ages were 7, 8, and 10 months. Dietary goals were the child's intake of energy ad libitum, fat at 30% to 35% of energy, cholesterol at less than 200 mg/d, and saturated, monounsaturated, and polyunsaturated fatty acids at a 1:1:1 ratio. Control families consumed an unrestricted diet. The apoE phenotype of 846 of the infants was determined; serum lipid and lipoprotein concentrations were measured at 7 and 13 months of age; and nutrient intakes were analyzed using 3-day food records at 8 and 13 months of age. RESULTS: At 7 months of age, serum cholesterol concentration was higher in apoE4-positive infants (E2/E4, E3/E4, and homozygous E4) than in apoE4-negative infants (159 +/- 31 mg/dL 4.10 +/- 0.81 mmol/L vs 150 +/- 29 mg/dL 3.89 +/- 0.74 mmol/L). The high-density lipoprotein cholesterol concentration was slightly lower in apoE4-positive infants than in apoE4-negative infants (34 +/- 8 mg/dL 0.88 +/- 0.20 mmol/L vs 35 +/- 7 mg/dL 0.91 +/- 0.19 mmol/L). Between 7 and 13 months of age, the serum cholesterol concentration in infants in the intervention group was unchanged, apoB concentration increased slightly, and apoA1 concentration decreased. In the control infants, serum cholesterol concentration increased 9 +/- 25 mg/dL (0.24 +/- 0.65 mmol/L), apoB concentration increased markedly, and apoA1 concentration was stable. Changes in serum lipid and apo concentrations that resulted from the dietary intervention were independent of the apoE phenotype. CONCLUSIONS: The apoE phenotype influenced serum cholesterol concentration markedly by 7 months of age. Between the ages of 7 and 13 months, a reduced saturated fat and cholesterol diet effectively prevented the age-associated increases in serum cholesterol and non-high-density cholesterol concentrations that were obvious in the control infants. The effects of the diet occurred in the infants independently of the apoE phenotype.

Apolipoprotein E polymorphism influences the serum cholesterol response to dietary intervention
Manttari, M., P. Koskinen, et al. (1991), Metabolism 40(2): 217-21.
Abstract: The association between apolipoprotein (apo) E polymorphism and the response of serum cholesterol to dietary counseling and to gemfibrozil treatment was investigated in 230 dyslipidemic middle-aged participants of the Helsinki Heart Study. Baseline lipid levels were not significantly different between subjects with or without the epsilon 4 allele. Following dietary counseling, participants with the epsilon 4 allele exhibited a greater reduction in serum total cholesterol (P less than.01) and low-density lipoprotein (LDL)-cholesterol (P less than.02) than those without the epsilon 4 allele, while the changes in high-density lipoprotein (HDL)-cholesterol and triglycerides were similar in the two groups. The alterations observed in total cholesterol, HDL-cholesterol, and triglycerides during treatment with gemfibrozil were not different between subjects with or without the epsilon 4 allele. The presence of the epsilon 4 allele and baseline serum cholesterol independently predicted the degree of cholesterol reduction following dietary counseling.

Apolipoprotein E polymorphism is associated with plasma cholesterol response in a 7-day hospitalization study for metabolic and dietary control in NIDDM
Murakami, K., M. Shimizu, et al. (1993), Diabetes Care 16(4): 564-9.
Abstract: OBJECTIVE--To investigate the effects of apolipoprotein E phenotype, which is an important genetic factor determining plasma cholesterol level, on plasma lipoprotein metabolism during a 7-day diet therapy of diabetes. RESEARCH DESIGN AND METHODS--Diet therapy was performed in 242 subjects with NIDDM. Plasma lipid levels and apolipoprotein A-I, B, and E levels on hospital days 2 and 9 were compared in three phenotype groups, epsilon 2 (E2/2, and E2/3), epsilon 3 (E3/3), and epsilon 4 (E3/4 and E4/4). RESULTS--No differences were observed in fasting blood glucose level, body mass index, age, duration of NIDDM, or medication among the three phenotype groups. Before starting the treatment, total plasma cholesterol did not vary by apolipoprotein E phenotype, although the mean plasma low-density lipoprotein cholesterol level in epsilon 4 patients was higher than in either epsilon 3 or epsilon 2 patients (epsilon 4, 145 +/- 42; epsilon 3, 131 +/- 34; epsilon 2, 128 +/- 36 mg/dl; P < 0.05). Changes in fasting blood glucose/body mass index after the 7-day treatment were not different among the apolipoprotein E phenotype groups, whereas the decrease in plasma cholesterol level after the treatment was significantly greater in epsilon 2 patients than in either epsilon 3 or epsilon 4 patients (epsilon 2, 10.3 +/- 14.2; epsilon 3, 6.1 +/- 11.0; epsilon 4, 3.8 +/- 9.6%; P < 0.05). CONCLUSIONS--Total plasma cholesterol response to in-hospital diet therapy varies by apolipoprotein E phenotypes, with subjects with apolipoprotein E2 showing the greatest response, whereas those with apolipoprotein E4 show the least. We suggest that subjects with apolipoprotein E4 should be controlled more strictly than other subjects from a viewpoint of reducing plasma cholesterol levels.

Apolipoprotein E produced by human monocyte-derived macrophages mediates cholesterol efflux that occurs in the absence of added cholesterol acceptors
Zhang, W. Y., P. M. Gaynor, et al. (1996), J Biol Chem 271(45): 28641-6.
Abstract: Human monocyte-derived macrophages can efflux accumulated cholesterol without exogenously added cholesterol acceptors (Kruth, H. S., Skarlatos, S. I., Gaynor, P. M., and Gamble, W. (1994) J. Biol. Chem. 269, 24511-24518). Most of the effluxed cholesterol accumulates in the medium as apolipoprotein E-discoidal lipid particles. In the current study, we determined whether and to what degree cholesterol efflux from human monocyte-macrophages depended on apolipoprotein E secretion. Unexpectedly, 2-week-old differentiated monocyte-macrophages secreted similar amounts of apolipoprotein E without or with cholesterol enrichment. Apolipoprotein E mRNA levels in these macrophages were not increased by cholesterol enrichment and were comparable with levels in HepG2 cells. Without cholesterol enrichment, monocyte-macrophages secreted lipid-poor apolipoprotein E with a density >1.21 g/ml. By contrast, cholesterol enrichment of monocyte-macrophages induced the association of apoE with phospholipid and cholesterol to form discoidal particles that floated at densities of 1.08-1.10 g/ml. An anti-apolipoprotein E monoclonal antibody added to the culture medium significantly inhibited cholesterol and phospholipid efflux from the monocyte-macrophages. This showed that apolipoprotein E was required for most of the cholesterol efflux, and that apolipoprotein E did not leave macrophages with lipid but rather associated with lipid after it was secreted. Thus, 1) apolipoprotein E was constitutively secreted by differentiated human monocyte-macrophages, 2) apolipoprotein E only formed discoidal particles following macrophage cholesterol enrichment, 3) apolipoprotein E was necessary for cholesterol efflux to occur in the absence of added cholesterol acceptors and, in addition 4) the level of macrophage unesterified cholesterol was not rate-limiting for this cholesterol efflux, and 5) net phospholipid synthesis occurred in macrophages secondary to apoE-mediated loss of macrophage phospholipid. In conclusion, apolipoprotein E functions in an autocrine pathway that mediates cholesterol efflux from human monocyte-derived macrophages.

Apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels
Raffai, R. L., S. M. Loeb, et al. (2005), Arterioscler Thromb Vasc Biol 25(2): 436-41.
Abstract: OBJECTIVE: The mechanisms by which apolipoprotein E (apoE) can promote the regression of atherosclerosis are not well understood. This study examined whether apoE can promote atherosclerosis regression independently of lowering plasma cholesterol levels. METHODS AND RESULTS: We studied hypomorphic apoE mice (Apoe(h/h)), which express an apoE4-like form of mouse apoE at approximately 2% to 5% of normal levels in plasma and are normolipidemic. After 18 weeks of diet-induced hypercholesterolemia, which resulted in advanced aortic atherosclerotic lesions composed of a lipid-rich layer of foam cells covering a fibrotic core, 2 groups of mice were fed a chow diet for 16 weeks. One group continued to express low levels of apoE; the other was induced to express physiological levels of plasma apoE by Cre-mediated recombination of the hypomorphic Apoe allele. In both groups, plasma cholesterol levels fell rapidly to similar levels, and histological analysis at 16 weeks revealed elimination of the foam-cell layer. However, physiological levels of plasma apoE also enhanced the removal of neutral lipids from the fibrotic cores. CONCLUSIONS: These findings demonstrate for the first time that apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Using Apoeh/hMx1-Cre mice we have begun to address apolipoprotein E-mediated mechanisms of atherosclerosis regression. We report the existence of a cholesterol-independent role of apolipoprotein E in atherosclerosis regression. This mechanism is critical for lipid removal from the fibrotic component of the plaque but not from the foam cell-rich layer beneath the endothelium.

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