Cholesterol Journal Articles

Record 9381 to 9400

Non-high density lipoprotein cholesterol and coronary events during long-term statin treatment
Athyros, V. G., A. A. Papageorgiou, et al. (2003), Atherosclerosis 168(2): 397-8.

Non-high density lipoprotein cholesterol is the best discriminator of myocardial infarction in young individuals
Rallidis, L. S., C. Pitsavos, et al. (2005), Atherosclerosis 179(2): 305-9.
Abstract: BACKGROUND: Several studies have shown that non-high density lipoprotein (HDL) cholesterol is a strong and independent predictor of cardiovascular events. We investigated whether non-HDL cholesterol can discriminate young individuals with myocardial infarction (MI) from age- and sex-matched controls. METHODS: We conducted a case-control study which included 100 consecutive patients who had survived their first MI before the age of 36 years and 100 age- and sex-matched healthy controls without a history of cardiovascular disease. Cardiovascular risk factors were reported and fasting lipids and apolipoproteins were measured. RESULTS: Patients with premature MI had significantly higher levels of total cholesterol, low density lipoprotein cholesterol, triglycerides, apolipoprotein B, lipoprotein (a) and non-HDL cholesterol and significantly lower levels of HDL cholesterol and apolipoprotein A. Multivariate logistic regression analysis showed that for every 10mg/dl increase in non-HDL cholesterol levels, the odds of having a MI were increased by 34% after controlling for age, sex, body mass index, presence of hypertension, diabetes and smoking habits. Moreover, participants in the highest tertile of non-HDL cholesterol levels had 28-fold higher odds for having a MI (95% confidence interval, 7.5-104.1), compared to those in the lowest tertile. Finally, discriminant analysis showed that non-HDL cholesterol (lambda-Wilks=0.68) was the strongest discriminator for MI among all studied risk factors while smoking (lambda-Wilks=0.80) was the strongest discriminator for MI among the non-lipid risk factors. CONCLUSIONS: Our study suggests that among conventional lipid and non-lipid risk factors non-HDL cholesterol is the best discriminator to predict the presence of MI in individuals under the age of 36 years.

Non-high-density lipoprotein cholesterol (non-HDL-C) as a predictor of cardiovascular mortality in patients with end-stage renal disease
Nishizawa, Y., T. Shoji, et al. (2003), Kidney Int Suppl(84): S117-20.
Abstract: BACKGROUND: Patients with end-stage renal disease (ESRD) often show lipid abnormalities that may promote atherosclerosis. Although the standard lipid marker is low-density lipoprotein cholesterol (LDL-C) in official recommendations, the need of fasting blood sampling has prevented routine screening for plasma lipids in hemodialysis patients. METHODS: We therefore evaluated the power of non-high-density lipoprotein cholesterol (non-HDL-C) in predialysis (non-fasting) serum as a predictor of cardiovascular mortality in a cohort of 525 hemodialysis patients. RESULTS: During the mean follow-up of 64 months, 120 deaths, including 44 fatal cardiovascular events, occurred. Patients in the highest tertile of non-HDL-C (137 to 285 mg/dL) had a significantly higher risk for cardiovascular mortality (HR, 3.065; 95% CI, 1.357 to 6.925; P = 0.007) correction in a univariate Cox analysis. The association between non-HDL-C and cardiovascular mortality remained significant in multivariate Cox models, which included HDL-C, age, gender, duration of hemodialysis, blood pressure, presence of diabetes mellitus, serum albumin, C-reactive protein, and body mass index. CONCLUSION: Non-HDL-C in predialysis serum was a significant and independent predictor of cardiovascular mortality in hemodialysis patients. Non-HDL-C may be a useful marker for risk assessment in routine practice, although predictive powers of this and the standard fasting LDL-C should be compared in future studies.

Non-high-density lipoprotein cholesterol and cardiovascular disease
Bittner, V. (2003), Curr Opin Lipidol 14(4): 367-71.
Abstract: PURPOSE OF REVIEW: Non-HDL cholesterol was designated a secondary target of therapy in the recent Adult Treatment Panel III report. This paper reviews correlates of non-HDL cholesterol levels and summarizes the available data on non-HDL cholesterol as a predictor of cardiovascular events as well as data linking treatment-induced changes in non-HDL cholesterol to cardiovascular outcomes. RECENT FINDINGS: Non-HDL cholesterol levels in the population vary by age, sex, and race and are closely linked to measures of adiposity, especially visceral adiposity. Several reports in populations with and without cardiovascular disease have recently been published that document the prognostic utility of non-HDL cholesterol levels. Preliminary data are also available to suggest that pharmacologically induced changes in non-HDL cholesterol levels relate to prognosis. SUMMARY: Non-HDL cholesterol is a potent predictor of cardiovascular risk among a broad range of individuals with and without cardiovascular disease and is prognostic over a wide range of follow-up periods. The impact of pharmacologically induced changes in non-HDL cholesterol on cardiovascular outcomes is less clear and requires further study.

Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality
Cui, Y., R. S. Blumenthal, et al. (2001), Arch Intern Med 161(11): 1413-9.
Abstract: BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) contains all known and potential atherogenic lipid particles. Therefore, non-HDL-C level may be as good a potential predictor of risk for cardiovascular disease (CVD) as low-density lipoprotein cholesterol (LDL-C). OBJECTIVES: To determine whether non-HDL-C level could be useful in predicting CVD mortality and to compare the predictive value of non-HDL-C and LDL-C levels. METHODS: Data are from the Lipid Research Clinics Program Follow-up Study, a mortality study with baseline data gathered from 1972 through 1976, and mortality ascertained through 1995. A total of 2406 men and 2056 women aged 40 to 64 years at entry were observed for an average of 19 years, with CVD death as the main outcome measure. RESULTS: A total of 234 CVD deaths in men and 113 CVD deaths in women occurred during follow-up. Levels of HDL-C and non-HDL-C at baseline were significant and strong predictors of CVD death in both sexes. In contrast, LDL-C level was a somewhat weaker predictor of CVD death in both. Differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 19% and 15%, respectively, in men. In women, differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 11% and 8%, respectively. CONCLUSIONS: Non-HDL-C level is a somewhat better predictor of CVD mortality than LDL-C level. Screening for non-HDL-C level may be useful for CVD risk assessment.

Non-high-density lipoprotein cholesterol level as potential risk predictor and therapy target
Grundy, S. M. (2001), Arch Intern Med 161(11): 1379-80.

Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI)
Bittner, V., R. Hardison, et al. (2002), Circulation 106(20): 2537-42.
Abstract: BACKGROUND: Current National Cholesterol Education Program guidelines recommend that non-high-density lipoprotein cholesterol (non-HDL-C) be considered a secondary target of therapy among individuals with triglycerides >2.26 mmol/L. It is not known whether non-HDL-C relates to prognosis among patients with coronary heart disease. METHODS AND RESULTS: Lipid levels were available at baseline among 1514 patients (73% men; mean age, 61 years) enrolled in the Bypass Angioplasty Revascularization Investigation (BARI); all had multivessel coronary artery disease. Patients were followed for 5 years. Outcomes of death, nonfatal myocardial infarction, and death or myocardial infarction were modeled using univariate and multivariate time-dependent proportional hazards methods; angina pectoris at 5 years was modeled using univariate and multivariate logistic regression. Non-HDL-C was a strong and independent predictor of nonfatal myocardial infarction (multivariate relative risk, 1.049 95% confidence intervals, 1.006 to 1.093 for every 0.26 mmol/L increase) and angina pectoris (multivariate odds ratio, 1.049 95% confidence intervals, 1.004 to 1.096 for every 0.26 mmol/L increase), but it did not relate to mortality. HDL-C and LDL-C did not predict events during follow-up. CONCLUSIONS: Among patients with lipid values in BARI, non-HDL-C is a strong and independent predictor of nonfatal myocardial infarction and angina pectoris at 5 years, even after consideration of powerful clinical variables. Our data suggest that non-HDL-C is an appropriate treatment target among patients with coronary heart disease.

Non-high-density lipoprotein cholesterol: a target of lipid-lowering in dialysis patients
Wanner, C. and V. Krane (2003), Am J Kidney Dis 41(3 Suppl 1): S72-5.
Abstract: BACKGROUND: The finding of an increased prevalence and levels of atherogenic lipoproteins in the context of normal plasma total and low-density lipoprotein (LDL) cholesterol (LDL-C) levels in hemodialysis (HD) patients highlights the need to look beyond the basic assessment of plasma concentrations of total cholesterol and LDL-C. Measurement of atherogenic lipoproteins (remnant lipoprotein particles RLPs, particularly intermediate-density lipoprotein IDL), is not routinely performed at the present time. METHODS: The National Cholesterol Education Program guidelines indicate that the secondary goal in persons with triglyceride levels greater than 200 mg/dL is non-high-density lipoprotein cholesterol (HDL-C). Non-HDL-C comprises all RLPs, including IDL, as well as atherogenic small dense LDL. RESULTS: We propose, for practical reasons, that non-HDL-C be used as a primary target in HD patients when lipid-lowering therapy is indicated. However, it remains unclear whether and how effective statins are in lowering remnant particle levels in dialysis patients. Recent data show that both simvastatin and atorvastatin reduce non-HDL-C levels effectively. Atorvastatin preferentially reduces RLP levels in patients with combined hyperlipidemia. CONCLUSION: The safety profile of statins predisposes prescription of this class of drugs to correct dyslipidemia or modulate lipoprotein particle composition in uremic patients. Whether atorvastatin influences myocardial infarction or all-cause mortality by adequately correcting dyslipidemia should be seen fairly quickly in the 1,252 dialysis patients with diabetes randomly assigned in the ongoing Die Deutsche Diabetes Dialyse study.

Non-high-density lipoprotein cholesterol: an alternate target for lipid-lowering therapy
Bittner, V. (2004), Prev Cardiol 7(3): 122-6; quiz 129-30.
Abstract: Non-high-density lipoprotein (non-HDL) cholesterol level is determined by subtracting the high-density lipoprotein cholesterol level from the total cholesterol level and thus encompasses not only low-density lipoprotein cholesterol, but also the cholesterol contained in atherogenic, triglyceride-rich particles like remnants. This review summarizes data extracted from English-language publications accessible through MEDLINE on the population distribution of non-HDL cholesterol, its relationship to cardiovascular disease, and the potential benefits of treatment. Non-HDL cholesterol levels in the population vary by age, sex, and race and are closely linked to measures of obesity, especially visceral obesity. Several studies in populations with and without cardiovascular disease show that non-HDL cholesterol levels relate to atherosclerosis severity and subsequent cardiovascular morbidity and mortality. Preliminary data also suggest that pharmacologically induced changes in non-HDL cholesterol levels relate to prognosis. In the National Cholesterol Education Program Adult Treatment Panel III report, non-HDL cholesterol has been designated a secondary target of therapy among patients with hypertriglyceridemia.

Non-high-density lipoprotein cholesterol: why lower is better
Garg, R., C. R. Vasamreddy, et al. (2005), Prev Cardiol 8(3): 173-7.
Abstract: Recent comparative trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) suggest that lower is better and that reducing low-density lipoprotein cholesterol (LDL-C) levels to below 100 mg/dL can provide additional clinical benefit. Non-high-density lipoprotein cholesterol (non-HDL-C) contains more atherogenic cholesterol than LDL-C and is considered a more accurate measurement of the total amount of atherogenic particles in the circulation. Therefore, the principle that "lower is better" may also apply to lowering levels of non-HDL-C. In persons with high triglycerides (200-499 mg/dL), LDL-C remains the primary target of therapy, but non-HDL-C is an important secondary therapeutic target. Non-HDL-C is strongly correlated with small dense LDL as well as apolipoprotein B, an established predictor of cardiovascular disease risk. Current evidence indicates that statins not only rapidly and dramatically reduce LDL-C, but also have a similar effect on non-HDL-C, and that the greater the reduction in LDL-C, the greater will be the reduction in non-HDL-C.

Non-insulin dependent diabetes and reverse cholesterol transport
Berthezene, F. (1996), Atherosclerosis 124 Suppl: S39-42.
Abstract: Quantitative and qualitative changes are observed in high-density lipoproteins (HDL) in patients with non-insulin dependent diabetes mellitus (NIDDM), and, more generally, in states of insulin resistance combined with central obesity. Reduced levels of HDL cholesterol are observed in patients with NIDDM, this decrease being correlated with the degree of insulin resistance. Qualitative changes in HDL are characterised by an increased triglyceride content, changes in the free cholesterol-phospholipid ratio, and an increase in the number of glycosylated apolipoprotein A-I molecules, giving rise to major variations in the viscosity of HDL particles. The transport of cholesterol is reduced when HDL is glycosylated and the transfer activity of cholesterol esters is increased. There is also a reduction in the level of HDL lipid peroxidation. These abnormalities in the lipid profile cause changes in reverse cholesterol transport which may be involved in the genesis of the accelerated atherosclerosis observed in patients with NIDDM.

Nonlinear relation between alcohol intake and high-density lipoprotein cholesterol level: results from the Copenhagen City Heart Study
Johansen, D., P. K. Andersen, et al. (2003), Alcohol Clin Exp Res 27(8): 1305-9.
Abstract: BACKGROUND: It has been suggested that the level of high-density lipoprotein cholesterol (HDL-C) in the blood can be used as a marker of recent alcohol intake. However, before using HDL-C as a predictor of alcoholism, the relation between alcohol intake and HDL-C in the entire range of consumption must be explored. Most studies model the relation between alcohol intake and HDL-C linearly, although a threshold effect is expected. The objective of this study was to evaluate the shape of the relation between intake of alcohol and HDL-C and to determine whether there are differential effects of beer, wine, and spirits on HDL-C and whether they remain after adjusting for total alcohol. METHOD: The relation between alcohol intake and HDL-C was investigated by means of generalized additive models using data from the Copenhagen City Heart Study. RESULTS: A nonlinear effect of alcohol improved the model fit significantly, and the nonlinearity of alcohol was highly significant in both men and women. The relation was concave: HDL-C was stable in men and women who drank more than approximately 35 and 20 drinks per week, respectively. We found a significant nonlinear term of wine on HDL-C in men after adjustment for total alcohol intake. CONCLUSIONS: There was a concave relation between alcohol intake and HDL-C, indicating a threshold effect of alcohol on HDL-C. The association between wine and HDL-C in men after adjusting for total alcohol intake may be due to residual lifestyle confounding.

Nonlinearity of high-density lipoprotein cholesterol determinations is matrix dependent
Kroll, M. H. and R. Chesler (1994), Clin Chem 40(3): 389-94.
Abstract: The majority of methods for determining high-density lipoprotein (HDL) cholesterol failed the 1991 College of American Pathologists (CAP) linearity survey (sets LN2-A, B, C). We hypothesized that they failed because of the survey material matrix. We evaluated linearity with dextran sulfate or phosphotungstate as the precipitating reagents for several methods: Ektachem; TDx; Sigma; Dimension; Cobas Fara, with Roche reagents; and the Hitachi 736, with precipitating reagents from Boehringer Mannheim Diagnostics. We tested CAP survey material, Sigma HDL-cholesterol control material, and a fresh serum pool for linearity, using the polynomial method. All of the methods were nonlinear for the CAP material and for the controls precipitated after dilution. Five of eight methods were linear for the control materials precipitated before dilution. All methods but one were linear for the serum pool. These results demonstrate that the source of the nonlinearity is located in the precipitation step and depends on the sample matrix.

Non-macrophage-related accumulation of cholesterol during probucol treatment in familial hypercholesterolemia: report of two cases
Nakamura, T., Y. Ueyama, et al. (1992), Atherosclerosis 92(2-3): 193-202.
Abstract: Two patients receiving long-term (3-4 years) treatment with probucol for familial hypercholesterolemia (FH) developed diffuse yellow lesions over the upper eyelids suggesting lipid storage in those tissues (diffuse lipid-storage lesions). Interestingly, each patient had shown a substantial reduction in their cholesterol levels together with a marked regression of their tendon xanthomas or typical xanthelasmas during treatment. To evaluate the role of probucol in this unusual finding we conducted histological and immunochemical evaluations of the lesions (removed surgically) and compared them with those of a non-probucol-treated subject with FH and typical audinal xanthelasma. In both probucol-treated patients the lesions were filled with foam cells and contained large amounts of cholesteryl ester. However, immunochemical analysis of the lesions of one patient using anti-monocyte monoclonal antibody (HAM56) demonstrated that they were not composed of macrophage-derived foam cells in contrast to those of the non-probucol-treated subject which stained clearly with anti-monocyte monoclonal antibody. In each case the foam cells did not react with muscle-actin-specific monoclonal antibody (HHF35). It appears that non-macrophage-related diffuse lipid-storage lesions may occur even during treatment with probucol despite the reduction in cholesterol levels and the regression of xanthomas, suggesting that probucol may alter the distribution of cholesterol from the macrophage to other cells.

Non-mucin proteins in the matrix of human cholesterol gallstones
Murray, F. E. and B. F. Smith (1991), Scand J Gastroenterol 26(7): 717-23.
Abstract: Human cholesterol gallstones contain a pigmented organic matrix that may originate from biliary sludge. The cholesterol gallstone matrix contains mucin, bile pigments, and calcium salts. The goal of this study was to examine whether non-mucin proteins are present in the matrix of cholesterol gallstones. Matrix was prepared from cholesterol gallstones from 18 patients. Proteins were identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and by molecular sieve high-performance liquid chromatography (HPLC). Two proteins were present in each gallstone and migrated with or just adjacent to standards of bovine serum albumin on SDS-PAGE. Several additional lower molecular weight proteins were identified, but not in every gallstone. Protein fractions contained visible pigment after chloroform extraction, and pigment co-eluted with proteins on HPLC, suggesting binding of pigments to proteins in the matrix. We conclude that low molecular weight proteins are present in the cholesterol gallstone matrix. The major protein appears to be serum albumin, although definitive identification has not been established. The origin of these matrix proteins and their possible significance in the pathogenesis of cholesterol cholelithiasis is unknown.

Nonopsonic phagocytosis of Mycobacterium kansasii by human neutrophils depends on cholesterol and is mediated by CR3 associated with glycosylphosphatidylinositol-anchored proteins
Peyron, P., C. Bordier, et al. (2000), J Immunol 165(9): 5186-91.
Abstract: Receptors involved in the phagocytosis of microorganisms under nonopsonic conditions have been little studied in neutrophils. Complement receptor type 3 (CR3) is a pattern recognition receptor able to internalize zymosan and C3bi-coated particles. We report that Abs directed against CR3 strongly inhibited nonopsonic phagocytosis of Mycobacterium kansasii in human neutrophils. In these cells CR3 has been found associated with several GPI-anchored proteins localized in cholesterol-rich microdomains (rafts) of the plasma membrane. Cholesterol sequestration by nystatin, filipin, or beta-cyclodextrin as well as treatment of neutrophils with phosphatidylinositol phospholipase C to remove GPI-anchored proteins from the cell surface markedly inhibited phagocytosis of M. kansasii, without affecting phagocytosis of zymosan or serum-opsonized M. kansasii. Abs directed against several GPI-anchored proteins inhibited phagocytosis of M. kansasii, but not of zymosan. N:-acetyl-D-glucosamine, which is known to disrupt interactions between CR3 and GPI proteins, also strongly diminished phagocytosis of these mycobacteria. In conclusion, phagocytosis of M. kansasii involved CR3, GPI-anchored receptors, and cholesterol. In contrast, phagocytosis of zymosan or opsonized particles involved CR3, but not cholesterol or GPI proteins. We propose that CR3, when associated with a GPI protein, relocates in cholesterol-rich domains where M. kansasii are internalized. When CR3 is not associated with a GPI protein, it remains outside of these domains and mediates phagocytosis of zymosan and opsonized particles, but not of M. kansasii.

Nonpharmacologic and pharmacologic treatment of patients with low levels of high-density lipoprotein cholesterol
Bowen, P. H. and J. R. Guyton (2000), Curr Atheroscler Rep 2(1): 58-63.
Abstract: Low levels of high-density lipoprotein cholesterol (HDL-C) constitute a strong risk factor for developing coronary heart disease. This risk can be decreased by even slight improvements in HDL-C levels. This review discusses both pharmacologic and nonpharmacologic treatments of patients with low levels of HDL-C, including lifestyle modifications and the benefits of oral estrogens, niacin, fibrates, statins, and combination drug therapy.

Nonpharmacologic management of low levels of high-density lipoprotein cholesterol
Ginsberg, H. N. (2000), Am J Cardiol 86(12A): 41L-45L.
Abstract: Several nonpharmacologic approaches can effectively increase low serum levels of high-density lipoprotein cholesterol (HDL-C), including weight control, specific nutritional choices, exercise, alcohol consumption, and smoking cessation. Increased visceral fat is inversely associated with HDL-C in both men and women. During weight reduction, HDL-C, HDL2-C, and apolipoprotein A-1 (apo A-1) tend to decrease, but levels increase with sustained weight loss. Overall, weight cycling is not detrimental in terms of serum lipids. Increasing monounsaturated fat intake and reducing carbohydrates increases HDL-C levels. Lowering trans-fatty acid intake also improves serum lipids. A very low-fat diet combined with stress-lowering lifestyle changes has been shown to cause regression of coronary artery disease. Moderate alcohol consumption, even in diabetic patients, and smoking cessation can increase serum HDL-C levels.

Nonphysiological overexpression of low-density lipoprotein receptors causes pathological intracellular lipid accumulation and the formation of cholesterol and cholesteryl ester crystals in vitro
Heeren, J., D. S. Steinwaerder, et al. (1999), J Mol Med 77(10): 735-43.
Abstract: Recent therapeutic strategies for the treatment of familial hypercholesterolemia have been based on liver-directed gene transfer of a functional low-density lipoprotein (LDL) receptor cDNA under control of viral or strong housekeeping promoters. Strong viral promoters including cytomegalovirus, Rous sarcoma virus, and simian virus 40 promoters are commonly employed to reach significant physiological effects. These promoters mediate constitutive and nonphysiological overexpression in every transduced cell, while the endogenous LDL receptor expression is controlled by a complex feedback mechanism based on intracellular cholesterol concentration. To investigate intracellular consequences of persistent LDL receptor overexpression we constructed a recombinant adenovirus encoding the human LDL receptor under control of the Rous sarcoma virus promoter. The metabolic and morphological effects of LDL receptor expression were characterized by uptake experiments with human hepatoma cells using fluorescent and radiolabeled LDL. We observed that large amounts of LDL accumulate within LDL receptor transduced cells, which eventually lead to massive intracellular lipid deposition. Kinetic experiments with LDL-supplemented medium resulted in numerous crystal shaped structures in the cytosol of transduced cells as visualized by digital interference contrast optic within 60 min after LDL supplementation. Thin layer chromatography analyses of cellular lipids suggested these crystalline structures to be dependent on intracellular cholesterol and cholesterol ester levels. Mock-infected cells showed neither cholesterol lipid accumulation nor crystal formation. In conclusion, our data demonstrate that nonphysiological overexpression of the LDL receptor can cause massive lipid accumulation, which cannot be compensated by the hepatoma cell metabolism. This phenomenon may result in negative selection of LDL receptor overexpressing cells in vitro and in vivo.

Non-physiological overexpression of the low density lipoprotein receptor (LDLr) gene in the liver induces pathological intracellular lipid and cholesterol storage
Cichon, G., T. Willnow, et al. (2004), J Gene Med 6(2): 166-75.
Abstract: BACKGROUND: Gene therapy of familial hypercholesterolemia (FH) requires successful transfer and lifelong expression of a functional low density lipoprotein receptor (LDLr) gene in the liver. Most of the vector systems currently employed for gene therapy use promoter elements which do not modulate transgene expression in a physiological manner. METHODS: To study the in vivo effects of constitutive LDLr gene expression in the absence of interfering immunological reactions we established a new mouse model which combines homozygous LDLr deficiency and severe combined immune deficiency (SCID). RESULTS: Adenovirus-mediated transfer and expression of the LDLr gene under the control of a commonly used virus-derived promoter (minimal CMV promoter) leads to prolonged reduction of serum cholesterol levels in LDLr-deficient SCID mice. During the first 10 days after gene therapy serum cholesterol drops to about 10% of pretherapeutic values. Serum cholesterol persists on this level for 2 weeks and then slowly starts to rise again. Four months after vector application serum levels have reached about 40% of pretherapeutic values. However, as early as 5 days after gene transfer, the histological analysis of liver sections revealed the formation of crystalline lipid/cholesterol deposits in the cytosol of hepatocytes. During the following 8 weeks the amount of crystals increased in size and density. The intracellular storage of lipid and cholesterol reduced cell viability and induced an accelerated loss of therapeutic DNA from mice livers as was shown in a comparative expression study employing a transgene with a different metabolic function (human alpha 1-antitrypsin). CONCLUSIONS: The non-physiological constitutive overexpression of an LDL receptor gene induces an imbalance between the speed of LDL uptake and metabolism which leads to pathological accumulation of lipids and cholesterol in hepatocytes. To protect cells from negative effects of LDLr overexpression, future vector design should consider the use of physiologically controlled expression elements.

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