High-density Apolipoprotein Research Articles

A Case of Familial Dysbetalipoproteinemia with Very Low Serum High-Density Lipoprotein-Cholesterol: Response to Atorvastatin Therapy

The mainstays of therapy of familial dyslipoproteinemia (FDB) are diet and long-term niacin or fibrate therapy. Statins are progressively recognized as accepted alternatives for FDB. We hereby describe the case of a 32-year-old obese man with treated panhypopituitarism and FDB, whose hyperlipidemia improved significantly on atorvastatin therapy. In this patient, we also noted a marked discrepancy between the serum high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo-) AI levels, with HDL-C being disproportionately low in comparison to the corresponding apo-AI values. Although atorvastatin therapy resulted in a significant improvement of lipid metabolism parameters within 8 weeks, the aforementioned discrepancy between HDL-C and apo-AI levels persisted. This case buttresses the effectiveness of atorvastatin therapy in FDB, and highlights the occurrence of discrepancy between HDL-C and measured apo-AI levels in rare cases of dyslipidemia. We speculate that the latter phenomenon may be caused by allelic variation(s) in any of three genes: apo-AI, apo-CIII, and apo-AIV.

Enhancement of Scavenger Receptor Class B Type I-mediated Selective Cholesteryl Ester Uptake fromapoA-I−/− High Density Lipoprotein (HDL) by Apolipoprotein A-I Requires HDL Reorganization by Lecithin Cholesterol Acyltransferase

The severe depletion of cholesteryl ester (CE) in adrenocortical cells of apoA-I(-/-) mice suggests that apolipoprotein (apo) A-I plays an important role in the high density lipoprotein (HDL) CE selective uptake process mediated by scavenger receptor BI (SR-BI) in vivo. A recent study showed that apoA-I(-/-) HDL binds to SR-BI with the same affinity as apoA-I(+/+) HDL, but apoA-I(-/-) HDL has a decreased V(max) for CE transfer from the HDL particle to adrenal cells. The present study was designed to determine the basis for the reduced selective uptake of CE from apoA-I(-/-) HDL. Variations in apoA-I(-/-) HDL particle diameter, free cholesterol or phospholipid content, or the apoE or apoA-II content of apoA-I(-/-) HDL had little effect on HDL CE selective uptake into Y1-BS1 adrenal cells. Lecithin cholesterol acyltransferase treatment alone or addition of apoA-I to apoA-I(-/-) HDL alone also had little effect. However, addition of apoA-I to apoA-I(-/-) HDL in the presence of lecithin cholesterol acyltransferase reorganized the large heterogeneous apoA-I(-/-) HDL to a more discrete particle with enhanced CE selective uptake activity. These results show a unique role for apoA-I in HDL CE selective uptake that is distinct from its role as a ligand for HDL binding to SR-BI. These data suggest that the conformation of apoA-I at the HDL surface is important for the efficient transfer of CE to the cell.

Increase of bile acids synthesis and excretion caused by taurine administration prevents the ovariectomy-induced increase in cholesterol concentrations in the serum low-density lipoprotein fraction of Wistar rats

We examined the effect of dietary taurine on the concentrations of serum cholesterol and apolipoprotein in lipoprotein fractions of Six-month-old ovariectomized, which were used as a model of hypercholesterolemia in postmenopausal woman, or sham operated rats. Taurine significantly reduced the serum total and low-density lipoprotein cholesterol concentrations only in the ovariectomized rats. In contrast, taurine significantly lowered the serum apolipoprotein B concentration and serum very low-density lipoprotein-apolipoprotein E concentration only in the sham operated rats. The serum total and high density lipoprotein-apolipoprotein E concentrations were significantly lower in the rats fed taurine than in those fed the control diet regardless of whether they had undergone ovariectomy. The esterified cholesterol level in the liver was significantly lower and the level of hepatic cholesterol 7α-hydroxylase activity was significantly higher in the rats fed taurine than in those fed the control diet. The total bile acids concentration in the feces and intestinal contents of rats fed taurine were significantly higher than those in rats fed the control diet regardless of whether they had undergone ovariectomy. In the sham-rats, taurine accelerated bile acid synthesis and excretion, thereby increasing cholesterol consumption. The increased cholesterol consumption might be compensated by accelerating cholesterol synthesis and/or reducing the synthesis and release of very low-density lipoprotein from the liver. But in the ovariectomized rats, although taurine also accelerated bile acid synthesis and excretion, cholesterol demand might be compensated by excess cholesterol in the blood.

3P-0895 The protective effect of estradiol in injury-elicited atheroma in mouse carotid artery is independent of NO and of the immune system

High density lipoprotein (HDL) cholesterol in apolipoprotein (apo) E-deficient mice is decreased. It has been suggested that apoA-I is lost from HDL in these mice because it must substitute for apoE as a structural protein for the abnormal cholesterol-rich lipoproteins. Therefore, we examined in vivo the influence of selective apoE expression on plasma HDL cholesterol in apoE-deficient mice. Bone marrow transplantation was used to establish macrophage-specific expression of apoE. Bone marrow transplantation normalized plasma triglycerides and significantly reduced total plasma cholesterol, but it did not increase hepatic apoA-I mRNA levels or total plasma apoA-I. Although total plasma apoA-I was not increased, HDL cholesterol measured following chromatographic separation was elevated twofold. Furthermore, plasma apoA-I was recovered from this HDL in animals expressing macrophage apoE. Compared to HDL of wildtype mice, this HDL had a similar chromatographic size distribution, but it lacked apoE and was more negatively charged. These studies indicated that plasma apoA-I distribution and HDL composition are influenced by apoE and that the abnormal apoA-I lipoprotein distribution of apoE-deficient mice can be altered in vivo by macrophage-derived apoE.

Serum Zinc in Healthy Belgian Children

Many reports mention marginal zinc status in childhood. Information on serum zinc (Zn) in Belgian children since the last reports are old and feeding habits are changing. Four hundred fifty-seven healthy children (0-14 yr, 262 boys) had a venipuncture after an overnight fast during a vaccination campaign. Serum Zn, alpha-tocopherol (alpha-T), cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo B), Apo A, and malondialdehyde (MDA) were determinated. The median Zn value is lower in infants than in older children (respectively 11.6 micromol/L vs 12.8 micromol/L). The type of infant feeding does not influence the serum Zn concentrations (breast-feeding, adapted, hypoallergenic, soy, or thickened). No children had increased serum MDA concentrations and the value is not influenced by the Zn concentration. Children presenting higher serum Zn values also have significantly higher serum alpha-T levels. In infants, there is a significant positive correlation between serum Zn and cholesterol, LDL-C, and Apo B. In this apparently healthy population, no signs of abnormal in vivo peroxidation of fatty acids are observed, even in the children with low serum Zn. More sensitive methods for the detection of peroxidation are necessary for determination of in vivo effects of marginal trace element status.

II. Rationale for Intervention

Cholesterol is a fat-like substance (lipid) that is present in cell membranes and is a precursor of bile acids and steroid hormones. Cholesterol travels in the blood in distinct particles containing both lipid and proteins (lipoproteins). Three major classes of lipoproteins are found in the serum of a fasting individual: low density lipoproteins (LDL), high density lipoproteins (HDL), and very low density lipoproteins (VLDL). Another lipoprotein class, intermediate density lipoprotein (IDL), resides between VLDL and LDL; in clinical practice, IDL is included in the LDL measurement. LDL cholesterol typically makes up 60-70 percent of the total serum cholesterol. It contains a single apolipoprotein, namely apo B-100 (apo B). LDL is the major atherogenic lipoprotein and has long been identified by NCEP as the primary target of cholesterol-lowering therapy. This focus on LDL has been strongly validated by recent clinical trials, which show the efficacy of LDL-lowering therapy for reducing risk for CHD. HDL cholesterol normally makes up 20-30 percent of the total serum cholesterol. The major apolipoproteins of HDL are apo A-I and apo A-II. HDL-cholesterol levels are inversely correlated with risk for CHD. Some evidence indicates that HDL protects against the development of atherosclerosis, although a low HDL level often reflects the presence of other atherogenic factors. The VLDL are triglyceride-rich lipoproteins, but contain 10-15 percent of the total serum cholesterol. The major apolipoproteins of VLDL are apo B-100, apo Cs (C-I, C-II, and C-III), and apo E. VLDL are produced by the liver and are precursors of LDL; some forms of VLDL, particularly VLDL remnants, appear to promote atherosclerosis, similar to LDL. VLDL remnants consist of partially degraded VLDL and are relatively enriched in cholesterol ester. Strictly speaking, IDL belongs to remnant lipoproteins although, in clinical practice, IDL is included in the LDL fraction. A fourth class of …

Hugh sinclair lecture: the regulation and remodelling of HDL by plasma factors.

High density lipoproteins (HDLs) originate as lipid-free or lipid-poor apolipoproteins that acquire most of their lipid in the extracellular space. They accept phospholipids from cells in a process promoted by the ATP binding cassette A1 transporter to form prebeta-migrating discoidal HDL that are efficient acceptors of cholesterol released from cell membranes. The cholesterol in discoidal HDL is esterified by lecithin:cholesterol acyltransferase (LCAT) in a process that converts the prebeta-migrating disc into an alpha-migrating, spherical HDL. Spherical HDL are further remodelled by cholesteryl ester transfer protein (CETP) that transfers cholesteryl esters from HDL to other lipoproteins and by hepatic lipase that hydrolyses HDL triglyceride in processes that reduce HDL size and lead to the dissociation of prebeta-migrating, lipid-poor apolipoprotein (apo)A-I from the particle. Prebeta-migrating, lipid-poor apoA-I is also generated as a product of the remodelling of HDL by phospholipid transfer protein. Thus, apoA-I cycles between lipid-poor and lipid associated forms as part of a highly dynamic metabolism of HDL. The other main HDL apolipoprotein, apoA-II is incorporated into apoA-I-containing particles in a process of particle fusion mediated by LCAT. Extracellular assembly and remodelling of HDL not only plays a major role in HDL regulation but also provides potential targets for therapeutic intervention. One example of this is the development of inhibitors of CETP.

Apolipoprotein E kinetics: influence of insulin resistance and type 2 diabetes.

Insulin resistance related to obesity and diabetes is characterized by an increase in plasma TG-rich lipoprotein concentrations. Apolipoprotein (apo) E plays a crucial role in the metabolism of these lipoproteins and particularly in the hepatic clearance of their remnants. The aim of this study was to explore apoE kinetics of obese subjects and to determine what parameters could influence its metabolism. Using stable-isotope labelling technique ([(2)H(3)]-leucine-primed constant infusion) and monocompartmental model (SAAM II computer software), we have studied the plasma kinetics of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) apoE in 12 obese subjects (body mass index (BMI) 27.4-36.6 kg/m(2)): Seven were type 2 diabetics (age 47-65 y; HbA1c 7.1-10.2%) and five were non-diabetics (age 40-51 y, HbA1c: 4.9-5.3%). Six of the diabetic subjects were insulin resistant as assessed by insulin sensitivity index (HOMA 2.6-10.0), while non-diabetic subjects were all insulin sensitive (HOMA 1.2-2.1). Plasma VLDL and HDL apoE concentrations were significantly higher in diabetic than in non-diabetic subjects (5.74+/-1.60 vs 1.46+/-1.74 mg/l, P<0.01 and 17.81+/-6.67 vs 9.97+/-3.32 mg/l, P<0.05). These increased levels were associated with significantly higher absolute production rate (APR) of VLDL and HDL apoE (0.714+/-0.343 vs 0.130+/-0.200 mg/kg/day, P<0.01, and 0.197+/-0.087 vs 0.080+/-0.060 mg/kg/day, P<0.05, respectively) while no significant difference was found for fractional catabolic rate (FCR) of VLDL and HDL apoE (3.44+/-1.64 vs 1.97+/-0.84/day and 0.30+/-0.12 vs 0.19+/-0.09/day, respectively). In the whole population, BMI was not correlated with any of apoE kinetic data. HOMA was positively correlated with FCR of VLDL apoE (r=0.64, P<0.05) and tended to be correlated with APR of VLDL apoE (r=0.58, P=0.06). HbA1c was positively correlated with APR and FCR of both VLDL apoE (r=0.91 and 0.78, P<0.01, respectively) and HDL apoE (r=0.66 and 0.69, P<0.05, respectively). Obese diabetics are characterized by elevated VLDL and HDL apoE levels associated with enhancement of VLDL and HDL apoE production rates. Whereas obesity did not influence apoE kinetic parameters in itself, insulin resistance may lead to an increase in VLDL apoE production and fractional catabolic rates. Diabetes and the glycemic control may also specifically influence the kinetics of both VLDL and HDL apoE. All together, these disorders should explain at least part of the increase in VLDL and HDL apoE observed in diabetes.

Effect of atorvastatin on high-density lipoprotein apolipoprotein A-I production and clearance in the New Zealand white rabbit.

HMG-CoA reductase inhibitors reduce the incidence of cardiovascular disease predominantly by their LDL-lowering effect. Recently, there has been great interest in the pleiotropic effects of statins, which appear to differ among the various agents in this class. Unlike other statins, atorvastatin exhibits a decline in its HDL-raising effect at higher doses in humans. Whether atorvastatin-mediated alterations in HDL turnover in vivo contribute to this effect has not previously been investigated. We therefore studied the effect of atorvastatin on HDL apolipoprotein (apo) A-I production and clearance in normolipidemic male New Zealand White rabbits. Kinetic studies of HDL-apoA-I radiolabeled with 131I were performed in chow-fed rabbits after 3 weeks of atorvastatin treatment of 5 mg x kg(-1) x d(-1) (n=7) versus placebo-treated rabbits (n=7). Our results showed a significantly (P<0.001) more rapid clearance ( approximately 2-fold) of HDL apoA-I in atorvastatin-treated animals compared with the control group (0.121+/-0.012 versus 0.061+/-0.004 pools/h, respectively), accompanied by a lesser 48% increase in the apoA-I production rate (3.84+/-0.38 versus 2.59+/-0.41 mg x kg(-1) x h(-1), P=0.06). Accordingly, plasma apoA-I levels in atorvastatin-treated animals declined significantly (P<0.05, n=8 animals) after 3 weeks of treatment (173.5+/-1.8 mg/dL) from baseline values. These data suggest that the effect on apoA-I levels observed with atorvastatin at higher drug doses in humans may be caused at least in part by enhanced HDL apoA-I catabolism, which is not entirely offset by a concomitant increase in apoA-I production. Whether this finding results from an effect of atorvastatin on HDL particle composition or on receptors involved in circulating HDL holoparticle clearance will require further study.

Effects of hormone replacement therapy and hepatic lipase polymorphism on serum lipid profiles in postmenopausal Japanese women.

The purpose of this study was to evaluate the relationships among hepatic lipase (HL) polymorphism, serum lipids, lipoproteins, and remnant-like particle cholesterol (RLP-C) and to determine the effects of hormone replacement therapy (HRT). We assessed the HL polymorphism in 209 postmenopausal Japanese women. Levels of serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein (Apo) AI, Apo B, Apo E, Apo CII, Apo CIII, and RLP-C were measured before and after 3 months of HRT. The frequency of each genotype was 32% for -514 C/C, 41% for C/T, and 27% for T/T. Subjects with the C/T and T/T genotypes had higher levels of HDL cholesterol and Apo AI than those with the C/C genotype. Those with the T/T genotype had higher levels of RLP-C than those with the C/C or C/T genotype. Serum total cholesterol, LDL cholesterol, Apo B, Apo E, and Apo CII were decreased, and HDL cholesterol and Apo AI were increased significantly in all genotypes after 3 months of HRT. There were no differences in these changes with genotype. The HL polymorphism was associated with higher levels of HDL cholesterol, Apo AI, and RLP-C, and the HL gene variation may contribute to HL activity and affect serum lipoprotein metabolism. Effects of HRT on serum lipids, lipoproteins, and remnant lipoprotein metabolism were unaffected by the HL polymorphism.

Alcohol Consumption Is Associated With Enrichment of High‐Density Lipoprotein Particles in Polyunsaturated Lipids and Increased Cholesterol Esterification Rate

Background Alcohol consumption is associated with high levels of high‐density lipoproteins (HDLs). Moreover, changes in the fatty acid patterns of red blood cell phospholipids and plasma lipids have been observed in drinkers. The objectives of this study were to characterize the composition of HDL particles with respect to lipid molecular species in regular wine drinkers and to assess the functional properties of those HDLs as regards key steps of reverse cholesterol transport.Methods Forty‐six subjects were recruited in the frame of a population study performed in Toulouse, southern France, and a nutritional investigation, including daily alcohol consumption, was performed. Subjects were sorted according to their daily alcohol intake (0, ≤35, and &gt;35 g/day), mostly as red wine. The plasma HDL fraction was isolated, and neutral lipid molecular lipids and phospholipid fatty acids were analyzed by gas liquid chromatography. Efflux of cellular cholesterol and rates of cholesterol esterification and cholesteryl ester transfers between lipoproteins were assayed in a cell‐plasma incubation system.Results Wine drinking, at 47 g/day, was associated with an increase in HDL cholesterol and apolipoprotein A‐I, but not with triglycerides. Isolated HDL displayed a 27% increase in all cholesteryl ester molecular species. The particles were also enriched in unsaturated phospholipids and, particularly, in those containing arachidonic (+30%) and eicosapentaenoic (+90%) acids. The plasma cholesterol esterification rate, reflecting lecithin cholesterol acyl transferase activity on HDL, was found to be higher (+27%) in drinkers than in nondrinkers, whereas the rate of cellular cholesterol efflux to plasma was identical.Conclusions Regular wine consumption is associated with high levels of polyunsaturated lipids in HDL and with increases in the cholesterol esterification rate.

Alcohol Consumption Is Associated With Enrichment of High-Density Lipoprotein Particles in Polyunsaturated Lipids and Increased Cholesterol Esterification Rate

Background Alcohol consumption is associated with high levels of high-density lipoproteins (HDLs). Moreover, changes in the fatty acid patterns of red blood cell phospholipids and plasma lipids have been observed in drinkers. The objectives of this study were to characterize the composition of HDL particles with respect to lipid molecular species in regular wine drinkers and to assess the functional properties of those HDLs as regards key steps of reverse cholesterol transport. Methods Forty-six subjects were recruited in the frame of a population study performed in Toulouse, southern France, and a nutritional investigation, including daily alcohol consumption, was performed. Subjects were sorted according to their daily alcohol intake (0, ≤35, and >35 g/day), mostly as red wine. The plasma HDL fraction was isolated, and neutral lipid molecular lipids and phospholipid fatty acids were analyzed by gas liquid chromatography. Efflux of cellular cholesterol and rates of cholesterol esterification and cholesteryl ester transfers between lipoproteins were assayed in a cell-plasma incubation system. Results Wine drinking, at 47 g/day, was associated with an increase in HDL cholesterol and apolipoprotein A-I, but not with triglycerides. Isolated HDL displayed a 27% increase in all cholesteryl ester molecular species. The particles were also enriched in unsaturated phospholipids and, particularly, in those containing arachidonic (+30%) and eicosapentaenoic (+90%) acids. The plasma cholesterol esterification rate, reflecting lecithin cholesterol acyl transferase activity on HDL, was found to be higher (+27%) in drinkers than in nondrinkers, whereas the rate of cellular cholesterol efflux to plasma was identical. Conclusions Regular wine consumption is associated with high levels of polyunsaturated lipids in HDL and with increases in the cholesterol esterification rate.

Apolipoprotein A-I Is Necessary for thein Vivo Formation of High Density Lipoprotein Competent for Scavenger Receptor BI-mediated Cholesteryl Ester-selective Uptake

The severe depletion of cholesteryl ester (CE) in steroidogenic cells of apoA-I(-/-) mice suggests that apolipoprotein (apo) A-I plays a specific role in the high density lipoprotein (HDL) CE-selective uptake process mediated by scavenger receptor BI (SR-BI) in vivo. The nature of this role, however, is unclear because a variety of apolipoproteins bind to SR-BI expressed in transfected cells. In this study the role of apoA-I in SR-BI-mediated HDL CE-selective uptake was tested via analyses of the biochemical properties of apoA-I(-/-) HDL and its interaction with SR-BI on adrenocortical cells, hepatoma cells, and cells expressing a transfected SR-BI. apoA-I(-/-) HDL are large heterogeneous particles with a core consisting predominantly of CE and a surface enriched in phospholipid, free cholesterol, apoA-II, and apoE. Functional analysis showed apoA-I(-/-) HDL to bind to SR-BI with the same or higher affinity as compared with apoA-I(+/+) HDL, but apoA-I(-/-) HDL showed a 2-3-fold decrease in the V(max) for CE transfer from the HDL particle to adrenal cells. These results indicate that the absence of apoA-I results in HDL particles with a reduced capacity for SR-BI-mediated CE-selective uptake. The reduced V(max) illustrates that HDL properties necessary for binding to SR-BI are distinct from those properties necessary for the transfer of HDL CE from the core of the HDL particle to the plasma membrane. The reduced V(max) for HDL CE-selective uptake likely contributes to the severe reduction in CE accumulation in steroidogenic cells of apoA-I(-/-) mice.

Separation and characterization of human high-density apolipoproteins using a nonaqueous modifier in capillary electrophoresis-mass spectrometry.

The separation and characterization of human apolipoproteins and their isoforms was investigated using capillary electrophoresis (CE) in combination with mass spectrometry (MS). The focus of these analyses was the major protein constituents of plasma high-density lipoproteins, apolipoprotein A-I and A-II. Using aqueous buffers in CE, no separation between apolipoprotein A-I and A-II was observed. With the addition of 10-20% acetonitrile, however, the two species could be separated. Furthermore, multiple peaks for each of the apolipoprotein species were observed under these CE conditions. In order to identify and characterize the components, these separations were then coupled with online mass spectrometric detection (CE-MS). Our CE-MS results suggest that the multiple components observed in the acetonitrile-containing CE separation appear to be oxidized forms of the proteins in addition to native forms of the apolipoprotein A-I and A-II. These data are in agreement with previous reports that the methionine residues of the high-density lipoproteins (HDLs) are sensitive to oxidation, which in turn, alters their lipid binding characteristics and secondary structure. In addition to oxidized forms of the proteins, apolipoprotein A-II contained additional components, which varied in mass by 128 Da. The structural differences between these components were determined by proteolytic digestion and tandem MS. Using these techniques, we determined that these components were due to truncation of the C-terminal glutamine amino acid residue on apolipoprotein A-II. These results demonstrate that CE in combination with MS is a promising technique for screening and characterizing isomers of plasma apolipoproteins.

Cholesteryl ester transfer protein expressed in lecithin cholesterol acyltransferase-deficient mice.

Regulation of plasma cholesteryl ester transfer protein (CETP) concentration was studied in lecithin-cholesterol acyltransferase (LCAT)-knockout mice. LCAT-knockout mice were cross-bred with CETP transgenic mice. The offspring (n=63) were classified for LCAT genotype and plasma CETP levels (no CETP, low CETP, and high CETP). High density lipoprotein (HDL) decreased as LCAT decreased in each CETP-level group. In the lcat(+/+) and lcat(+/-) mice, plasma CETP varied from 0 to 30 micro g/mL, whereas it was <10 micro g/mL in the lcat(-/-) mice. HDL cholesterol and phospholipid decreased and HDL triglyceride and apolipoprotein B increased in CETP in the lcat(+/+) and lcat(+/-) mice, whereas there was no difference in HDL between low and high CETP. An effect of CETP on HDL was not detected in the lcat(-/-) mice because of the absence of mature HDL. Genomic DNA and mRNA of CETP were correlated and were similar in the lcat(-/-) and lcat(+/+) mice. Plasma CETP was correlated with its genomic DNA and mRNA, but the slope of the increase was much lower in the lcat(-/-) mice. Whereas plasma CETP mostly associates with HDL in the lcat(+/+) mouse, it is found free in the lcat(-/-) mouse. Plasma CETP is posttranscriptionally downregulated in the lcat(-/-) mice, presumably by its extremely low HDL.

Lipids and pulmonary function in the Third National Health and Nutrition Examination Survey.

Studies considering the association between total cholesterol and noncardiovascular mortality, particularly from respiratory disease, yield inconclusive findings. To explore this question, the relation of lipids to pulmonary function, specifically forced expiratory volume in 1 second (FEV(1)), was investigated in the Third National Health and Nutrition Examination Survey. Conducted in the United States in 1988-1994 among adults aged > or =17 years, this survey measured serum lipids, FEV(1), and confounding factors including smoking and antioxidants. Multiple linear regression analysis explored the relation of FEV(1)/height(2) to low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and their respective apolipoproteins (apo) B and A-I. A standard deviation increase in HDL cholesterol or apo A-I was associated with an FEV(1) increase of 43 ml (95% confidence interval (CI): 30, 56) or 29 ml (95% CI: 11, 47), respectively, for an average-height adult. A standard deviation increase in LDL cholesterol or apo B was associated with an FEV(1) decrease of -24 ml (95% CI: -43, -5) or -53 ml (95% CI: -74, -32), respectively, adjusted for serum antioxidant status. The lipid subfractions were differentially associated with FEV(1) consistent with the possibility that LDL cholesterol contributes to endogenous oxidative burden while HDL cholesterol attenuates inflammatory tissue damage. Whether these associations are causal remains to be determined.

Cloning and Characterization of a Novel Apolipoprotein A-I Binding Protein, AI-BP, Secreted by Cells of the Kidney Proximal Tubules in Response to HDL or ApoA-I

Apolipoprotein A-I (apoA-I) is the major apolipoprotein of high-density lipoproteins (HDL) and has an important role in the regulation of the stability, lipid transport, and metabolism of HDL particles. To identify novel proteins that are involved in HDL metabolism, we used mature apoA-I (amino acids 25–267) as a bait for the screening of a human liver two-hybrid cDNA library. Among the identified genes, several encoded known proteins, including serum amyloid A2a (SAA2a), apoC-I, and phosphodiesterase HCAM1 (PDE1A), found to interact with apoA-I. In addition, we have cloned a novel 29 kDa apoA-I interacting protein, which we named AI-BP (apoA-I binding protein). The AI-BP encoding gene, APOA1BP, which is located on chromosome 1q21, is composed of six exons and five introns and spans 2.5 kb. Northern blot analysis demonstrated ubiquitous expression of the APOA1BP mRNA with the highest expression in kidney, heart, liver, thyroid gland, adrenal gland, and testis. AI-BP protein is not detectable in serum of healthy probands, but serum samples of patients with septic syndromes may contain elevated levels of AI-BP. Significant amounts of AI-BP protein are found in cerebrospinal fluid and urine of healthy probands. The stimulation of cells derived from the kidney proximal tubules with apoA-I or HDL induces a concentration-dependent secretion of AI-BP indicating an important role for AI-BP, in the renal tubular degradation or resorption of apoA-I.

Prevention of Bone Loss With Tibolone in Postmenopausal Women: Results of Two Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Studies

Tibolone is a synthetic agent with tissue-specific effects, including an antiresorptive effect on bone. Clinical trials have documented prevention of bone loss in postmenopausal women; a daily oral dose of 2.5 mg has generally been used. The present study evaluated tibolone therapy over 2 years with daily doses of 0.3, 0.625, 1.25, or 2.5 mg of tibolone as compared with placebo in 770 generally healthy women who were 1 to 4 years past menopause and who had normal bone density for their age. All of them took supplemental calcium carbonate as well in a daily dose of 500 mg. Bone mineral density (BMD) was measured in the lumbar spine and right proximal femur by dual-energy x-ray absorptiometry for up to 2 years. The patient population was drawn from two identically designed randomized, placebo-controlled, dose-finding studies. A total of 519 women completed the 2-year studies. Tibolone led to a progressive increase in spinal and total hip BMD over 2 years of treatment in all doses except 0.3 mg. Hip BMD was maintained by the 0.3-mg dose. Only doses of 1.25 or 2.5 mg daily progressively increased BMD at the femoral neck. Differences in mean percentage of change from baseline in spinal and total hip BMD were significant for all dose groups compared with placebo. The rise in BMD at the lumbar spine over baseline, with 1.25 or 2.5 mg daily, was 2.0 to 2.6% at 2 years, a statistically significant and clinically meaningful effect. Increasing BMD was not limited to the first year of tibolone therapy. All tibolone doses except the lowest were associated with decreased serum osteocalcin levels, whereas in placebo recipients osteocalcin increased over baseline. Comparable reductions in bone-specific alkaline phosphatase were noted in patients given 1.25 and 2.5 mg of tibolone. Total cholesterol levels decreased in all tibolone dose groups, but declines in high-density lipoprotein cholesterol, triglycerides, and apolipoprotein A-1 seemed to be dose-related. All doses of tibolone were generally well tolerated during the 2 years of administration. No deep venous thrombosis or pulmonary embolism was observed. Hot flashes were less frequent with tibolone therapy than with placebo and were at their lowest with the 2.5-mg dose. Average body weight changes were similar in the actively treated and placebo groups. Endometrial hyperplasia was comparably frequent in the two groups. Vaginal bleeding became less prevalent with continued tibolone treatment. A 1.25-mg daily dose of tibolone is recommended for preventing osteoporosis. The ability of this drug to dose-dependently increase BMD in the lumbar spine and total hip should allow individualized antiresorptive treatment for postmenopausal women according to their clinical response.

Effect of Alcohol on Lipids and Lipoproteins in Relation to Atherosclerosis

Several studies indicate that light-to-moderate alcohol consumption is associated with a low prevalence of coronary heart disease. An increase in high-density lipoprotein (HDL) cholesterol is associated with alcohol intake and appears to account for approximately half of alcohol's cardioprotective effect. In addition to changes in the concentration and composition of lipoproteins, alcohol consumption may alter the activities of plasma proteins and enzymes involved in lipoprotein metabolism: cholesteryl ester transfer protein, phospholipid transfer protein, lecithin: cholesterol acyltransferase, lipoprotein lipase, hepatic lipase, paraoxonase-1 and phospholipases. Alcohol intake also results in modifications of lipoprotein particles: low sialic acid content in apolipoprotein components of lipoprotein particles (e.g., HDL apo E and apo J) and acetaldehyde modification of apolipoproteins. In addition, “abnormal” lipids, phosphatidylethanol, and fatty acid ethyl esters formed in the presence of ethanol are associated with lipoproteins in plasma. The effects of lipoproteins on the vascular wall cells (endothelial cells, smooth muscle cells, and monocyte/macrophages) may be modulated by ethanol and the alterations further enhanced by modified lipids. The present review discusses the effects of alcohol on lipoproteins in cholesterol transport, as well as the novel effects of lipoproteins on vascular wall cells.

Assessment of the metabolic tolerance in postmenopausal women over a 1-year period of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone

This double-blind, randomized, multi-center study compared the metabolic tolerance of a combined formulation containing estradiol (E2) and trimegestone (TMG) with a standard hormone replacement therapy(HRT) containing estradiol valerate (EV) and norgestrel (NG). Blood lipids, glucose and fibrinogen concentrations were measured in the study which was conducted over 13 cycles, each of 28 days, and included634 subjects in two randomized groups. A total of 481 subjects completed the study. The circulating concentrations of high density lipoprotein (HDL), HDL2, HDL3 cholesterol and apolipoprotein A1 were increasedin the E2 + TMG group and reduced in the EV + NG group. Total cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein(a) concentrations were decreased in both treatmentgroups; however, the reduction in LDL cholesterol was greater in the E2 + TMG group. Similar lipid findings were found in a subgroup that excluded subjects who had less than 3 months washout from a previousHRT, who provided a blood sample outside the day 17-28 window, or who were taking beta-blockers or thiazide diuretics. Blood glucose concentrations were reduced slightly in both treatment groups. A significantreduction in fibrinogen was also seen in both groups over the course of the study. The changes in lipid profile, especially HDL cholesterol, were more beneficial in the E2 + TMG group in comparison withthe EV + NG group. This reflects the lack of androgenic action of trimegestone in comparison with norgestrel, which exhibits an androgenic effect and prevents the estrogen-induced increase in HDL cholesterol.The results of the study suggest that the use of trimegestone in combination with E2 may be preferable to norgestrel because of the more favorable lipid profile.