Reduced HDL-cholesterol Levels Research Articles

Identification of a Novel Polymorphism in X-Linked Sterol-4-Alpha-Carboxylate 3-Dehydrogenase (Nsdhl) Associated with Reduced High-Density Lipoprotein Cholesterol Levels in I/LnJ Mice

Loci controlling plasma lipid concentrations were identified by performing a quantitative trait locus analysis on genotypes from 233 mice from a F2 cross between KK/HlJ and I/LnJ, two strains known to differ in their high-density lipoprotein (HDL) cholesterol levels. When fed a standard diet, HDL cholesterol concentration was affected by two significant loci, the Apoa2 locus on Chromosome (Chr) 1 and a novel locus on Chr X, along with one suggestive locus on Chr 6. Non-HDL concentration also was affected by loci on Chr 1 and X along with a suggestive locus on Chr 3. Additional loci that may be sex-specific were identified for HDL cholesterol on Chr 2, 3, and 4 and for non-HDL cholesterol on Chr 5, 7, and 14. Further investigation into the potential causative gene on Chr X for reduced HDL cholesterol levels revealed a novel, I/LnJ-specific nonsynonymous polymorphism in Nsdhl, which codes for sterol-4-alpha-carboxylate 3-dehydrogenase in the cholesterol synthesis pathway. Although many lipid quantitative trait locus have been reported previously, these data suggest there are additional genes left to be identified that control lipid levels and that can provide new pharmaceutical targets.

Effects of cigarette smoking on HDL quantity and function: Implications for atherosclerosis

Cigarette smoking has been identified as an independent and preventable risk factor for atherosclerosis and cardiovascular disease. Population studies have shown that plasma high density lipoprotein (HDL) cholesterol levels are inversely related to the risk of developing cardiovascular disease. Cigarette smoking is associated with reduced HDL cholesterol levels. Cigarette smoking can alter the critical enzymes of lipid transport, lowering lecithin: cholesterol acyltransferase (LCAT) activity and altering cholesterol ester transfer protein (CETP) and hepatic lipase activity, which attributes to its impact on HDL metabolism and HDL subfractions distribution. In addition, HDL is susceptible to oxidative modifications by cigarette smoking, which makes HDL become dysfunctional and lose its atheroprotective properties in smokers. Therefore, cigarette smoking has a negative impact on both HDL quantity and function, which can explain, in part, the increased risk of cardiovascular disease in smokers.

Incidence of total knee and hip replacement for osteoarthritis in relation to the metabolic syndrome and its components: A prospective cohort study

ObjectiveTo examine whether components of metabolic syndrome (MetS), either singly or additively, were associated with the incidence of severe knee and hip OA, and whether these associations were independent of obesity assessed by body mass index (BMI). MethodsTwenty thousand, four hundred and thirty participants who had blood lipids, anthropometric and blood pressure measurements during 2003–2007 were selected from the Melbourne Collaborative Cohort Study. MetS was defined as central obesity assessed by waist circumference and any two of raised triglyceride level, reduced HDL cholesterol level, hypertension or impaired fasting glycaemia. The incidence of total knee and hip replacement was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. ResultsSix hundred and sixty participants had knee OA and 562 had hip OA. After adjustment for age, gender, country of birth, education, physical activity and BMI, central obesity [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.25–2.01] and hypertension (1.24, 1.05–1.48) were associated with increased risk of knee OA. The accumulation of MetS components was associated with knee OA risk, independent of BMI: one component, 2.12 (1.15–3.91); two components, 2.92 (1.60–5.33) and three or more components, 3.09 (1.68–5.69). No statistically significant associations were observed for hip OA. ConclusionCumulative number of MetS components and central obesity and hypertension were associated with increased risk of severe knee OA, independent of BMI. No associations were observed with severe hip OA. These findings suggest that the pathogenesis of knee and hip OA differ and that targeting the management of MetS may reduce the risk of knee OA.

Ezetimibe enhances macrophage reverse cholesterol transport in Golden Syrian hamsters

Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. RCT from macrophages (macrophage RCT) is a critical mechanism of anti-atherogenecity of high-density lipoproteins (HDL). An inhibitor of cholesterol absorption, ezetimibe, reportedly promotes macrophage RCT in mice lacking cholesterol ester transfer protein (CETP), we therefore investigated it in hamsters. ![Figure][1] Figure 1 As shown in Figures, high-cholesterol diet (HCD) increased cholesterol levels in overall lipoprotein fractions (very low-density/low-density lipoproteins, VLDL/LDL/HDL). Ezetimibe markedly reduced VLDL/LDL cholesterol levels under both normal chow (NC) and HCD; however, did not affect under NC and rather reduced HDL-cholesterol levels under HCD. Macrophage RCT assay revealed that HCD increased hepatic levels of 3H-cholesterol derived from pre-labeled macrophages intraperitoneally injected; in contrast, reduced it in bile, both of which were completely cancelled by ezetimibe. Despite of reduced tracer level in liver, ezetimibe enhanced fecal excretion of 3H-sterol under both NC and HCD. Interestingly, enhanced fecal excretion of sterol was mainly contributed by that of cholesterol, but not bile acids. Finally, ezetimibe did not affect macrophages cholesterol efflux capacity of HDL obtained from the hamsters, suggesting that the stimulatory effect of ezetimibe on RCT in vivo was independent of HDL quantity/quality. In conclusion, ezetimibe exerts an additive anti-atherogenic property by enhancing RCT in CETP-expressing animals, hamster, and possibly human. Our data also imply that unknown pathways, such as trans-intestinal cholesterol excretion, might contribute RCT promotion by ezetimibe. [1]: pending:yes

Associations of acanthosis nigricans with metabolic abnormalities in polycystic ovary syndrome women with normal body mass index

Acanthosis nigricans (AN) usually correlates to insulin resistance (IR) or obesity in obese populations, but adequate studies on the significance of AN in people with normal body mass index (BMI) have not been performed and discussed. Three hundred and thirty-nine polycystic ovary syndrome (PCOS) patients with normal BMI (<23kg/m(2) ) were recruited. The anthropometric and biochemical parameters of these patients were measured. In these patients with normal BMI, 33 (9.7%) women had AN, and six (1.77%) women were diagnosed with metabolic syndrome. Most of the anthropometric and biochemical variables associated with metabolic status were more unfavorable in the AN-positive group compared with the AN-negative groups. The prevalence of central obesity, IR and reduced high-density lipoprotein cholesterol (HDL-C) level were also significantly higher in the AN-positive group (P<0.05). In multiple regression analysis, presence of AN was still significantly associated with IR (odds ratio [OR]=2.952, 95% confidence intervals [CI]=1.367-6.376] and reduced HDL-C level (OR=2.668, 95% CI=1.160-6.135) after adjustments for age and BMI. Sensitivity, specificity, and positive and negative predictive values for AN to detect IR were 18.6%, 92.6%, 39.4% and 81.4%, respectively. In conclusion, presence of AN correlated with IR and reduced HDL-C level in PCOS women with normal BMI. AN status had high specificity to detect IR, but lack of sensitivity.

Pathophysiology of Human Visceral Obesity: An Update

Excess intra-abdominal adipose tissue accumulation, often termed visceral obesity, is part of a phenotype including dysfunctional subcutaneous adipose tissue expansion and ectopic triglyceride storage closely related to clustering cardiometabolic risk factors. Hypertriglyceridemia; increased free fatty acid availability; adipose tissue release of proinflammatory cytokines; liver insulin resistance and inflammation; increased liver VLDL synthesis and secretion; reduced clearance of triglyceride-rich lipoproteins; presence of small, dense LDL particles; and reduced HDL cholesterol levels are among the many metabolic alterations closely related to this condition. Age, gender, genetics, and ethnicity are broad etiological factors contributing to variation in visceral adipose tissue accumulation. Specific mechanisms responsible for proportionally increased visceral fat storage when facing positive energy balance and weight gain may involve sex hormones, local cortisol production in abdominal adipose tissues, endocannabinoids, growth hormone, and dietary fructose. Physiological characteristics of abdominal adipose tissues such as adipocyte size and number, lipolytic responsiveness, lipid storage capacity, and inflammatory cytokine production are significant correlates and even possible determinants of the increased cardiometabolic risk associated with visceral obesity. Thiazolidinediones, estrogen replacement in postmenopausal women, and testosterone replacement in androgen-deficient men have been shown to favorably modulate body fat distribution and cardiometabolic risk to various degrees. However, some of these therapies must now be considered in the context of their serious side effects. Lifestyle interventions leading to weight loss generally induce preferential mobilization of visceral fat. In clinical practice, measuring waist circumference in addition to the body mass index could be helpful for the identification and management of a subgroup of overweight or obese patients at high cardiometabolic risk.

Perturbations in the HDL metabolic pathway predispose to the development of osteoarthritis in mice following long-term exposure to western-type diet

Recent data suggest that obesity and related metabolic aberrations are associated with osteoarthritis (OA) development, a phenomenon that is attributed at least in part to the consumption of lipid-rich diets. To date, the molecular mechanisms that govern the lipid-OA connection remain largely unknown. Given the important role of high-density lipoprotein (HDL) in plasma and tissue lipid metabolism, the main purpose of the present study was to investigate the role of HDL metabolism in the pathobiology of OA. We used apolipoprotein A-I (apoA-I)(-/-) mice that lack classical apoA-I containing HDL, LCAT(-/-) mice that have only immature HDL and relatively reduced HDL-cholesterol levels and control C57BL/6 mice. Mice were placed on chow or western-type (WTD) and monitored for 24 weeks. Knee joints were removed and articular cartilage was isolated for further analyses. The LCAT(-/-) mice were significantly more sensitive to the development of diet-induced obesity compared to the C57BL/6 and apoA-I(-/-) mice. Morphological, biochemical and molecular analyses revealed that the LCAT(-/-) obese mice developed OA, while the C57BL/6 mice that were fed WTD did not. Notably, apoA-I(-/-) mice that received WTD also developed OA although their body-weight gain was similar to their wild-type counterparts. Interestingly, bone marrow from LCAT(-/-) and apoA-I(-/-) mice contained significantly increased number of adipocytes, compared to the other groups. Our findings suggest that perturbations in HDL metabolism predispose to OA following chronic insult with WTD and raise the challenging possibility that HDL has a causative relation to OA in patients with metabolic syndrome.

PERBEDAAN KADAR KOLESTEROL LDL DAN HDL ANTARA WANITA VEGETARIAN TIPE VEGAN DAN NON-VEGAN

ABSTRACTBackground: Studies which investigated different risk for cardiovascular disease in vegetarian reported that each vegetarian diet type had different lipid serum level. Elevated LDL cholesterol level and reduced HDL cholesterol level are independent risk factors for coronary heart disease. This study was aimed to compare levels on LDL and HDL cholesterol between vegetarian vegan and non-vegan.Methods: Two groups of vegetarian women, 23 people in each group of vegan and non-vegan, participated in this cross-sectional study. The data taken of each subject were nutrient intakes (total fat, PUFA, MUFA, SFA, cholesterol, and total fiber), physical activity, body weight, height, LDL and HDL cholesterol serum levels. Data were analyzed by Shapiro-Wilk test, independent-t test, Mann-Whitney test and ANACOVA test.Results: There were no significant differences on LDL and HDL cholesterol serum levels between vegetarian vegan and non-vegan, both before and after variables i.e age, physical activity, body mass index (BMI), amount of total fat, PUFA, MUFA, SFA, cholesterol, and total fiber adjusted (p &gt; 0,05). LDL cholesterol levels for vegetarian vegan and non-vegan were respectively: 97,8 ± 54,87 mg/dl and 112,6 ± 36,03 mg/dl, while for HDL cholesterol, those levels were 54,9 ± 11,15 mg/dl and 55,2 ± 10,82 mg/dl. In multivariant analysis, the most influential variables on LDL cholesterol serum level were age (p = 0,001) and physical activity (p = 0,010), while for HDL serum cholesterol were BMI (p = 0,010) and total fat (p = 0,012). This study also found the significant difference of BMI between vegetarian vegan and non-vegan (p = 0,011), whose for each of groups’ BMI, were respectively: 20,9 ± 3,08 kg/m2 and 23,5 ± 3,53 kg/m2. Conclusion: LDL and HDL cholesterol serum levels are not different between vegetarian vegan and non-vegan. BMI of both groups is different. Age and physical activity affect on LDL serum cholesterol level, while BMI and total fat affect on HDL serum cholesterol level. LDL cholesterol serum level and BMI in vegetarian vegan are lower than non-vegan. Key words: Vegetarian diet, vegan, non-vegan, LDL cholesterol, HDL cholesterol

The Effects of Apolipoprotein F Deficiency on High Density Lipoprotein Cholesterol Metabolism in Mice

Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20–25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/−0.9 mg/dl vs. WT: 1.2+/−0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls.

Response: Prevalence of Dyslipidemia among Korean Adults: Korea National Health and Nutrition Survey 1998-2005 (Diabetes Metab J 2012;36:43-55)

I deeply appreciate the comments of Dr. Bo Kyung Koo on our study Prevalence of dyslipidemia among Korean adults: Korea National Health and Nutrition Survey 1998-2005 which was published in Diabetes & Metabolism Journal 2012;36:43-55. Metabolic syndrome is a cluster of multiple cardiometabolic risk factors, and prevalence of the syndrome is expected to increase in Korea [1,2]. However, as Dr. Koo noted, common definitions of metabolic syndrome do not include elevated low density lipoprotein cholesterol (LDL-C) level, which is strongly associated with atherosclerotic cardiovascular disease [3,4]. Dr. Koo also mentioned that evaluation of lipid abnormalities can provide additional predictive value compared to the presence of metabolic syndrome. This is an important comment and the reason why we reported prevalence of different forms of dyslipidemia including elevated total cholesterol, elevated triglycerides, elevated LDL-C, and reduced high density lipoprotein cholesterol (HDL-C). Dr. Koo raised an epidemiologically and clinically relevant issue regarding the definition of low HDL-C level. In defining metabolic syndrome, the cutoff level of low HDL-C is frequently higher for women because women have a higher HDL-C distribution compared to men. According to the definition of metabolic syndrome in the NCEP-ATP III guidelines, reduced HDL-C level is defined as <50 mg/dL in women and <40 mg/dL in men [3]. However, the NCEP-ATP III criteria for reduced HDL-C might not be appropriate for the Korean population. Compared to the Western population, East Asian populations have lower HDL-C level and show smaller sex differences for this measure. Moreover, HDL-C levels among Koreans are even lower than those of other East Asian populations and show only a small sex difference [5-8]. In our study, the sex difference in mean HDL-C (women minus men) was only 2.1 mg/dL in 1998, 3.6 mg/dL in 2001, and 5.0 mg/dL in 2005 [9]. Because Korean women have relatively low HDL-C levels, 58.5% of women had an HDL-C level lower than 50 mg/dL in the 2001 KNHANES [10]. This caused the unusually high prevalence of metabolic syndrome, in comparison to the low prevalence of obesity, among Korean women in the literature. We also lack direct data regarding the level of HDL-C that should be treated. It is unclear whether women with HDL-C level of 40 to 49 mg/dL but without other lipid abnormalities should be treated. For these reasons, some Asian studies have used a cutoff for reduced HDL-C of <40 mg/dL for both sexes [6,11]. Overall, I appreciate and agree with Dr. Koo's considerate comments. Great attention should be given to the working definitions when reporting and interpreting prevalence of metabolic syndrome and dyslipidemia. Further studies are also required to establish an appropriate definition of dyslipidemia in the Korean population.

Effect of Probucol on Antioxidant Properties of HDL in Patients with Heterozygous Familial Hypercholesterolemia

High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol. Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chromatography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity. Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.

Pharmacologic Suppression of Hepatic ATP-Binding Cassette Transporter 1 Activity in Mice Reduces High-Density Lipoprotein Cholesterol Levels but Promotes Reverse Cholesterol Transport

The role of hepatic ATP-binding cassette transporter 1 (ABCA1) in maintaining plasma high density lipoprotein cholesterol (HDL-C) levels is well established, but its role in reverse cholesterol transport (RCT) is unclear. Probucol is a compound that reduces HDL-C levels but also reduces atherosclerosis in animal models and xanthomas in humans. The aim of the present study was to test the hypothesis that probucol inhibits hepatic ABCA1 activity, thereby reducing HDL-C levels but promoting RCT from macrophages. Wild-type (WT) C57BL/6 mice and scavenger receptor class B type I (SR-BI) knockout mice were fed a chow diet containing 0.5% probucol or normal chow for 2 weeks. In WT mice, probucol, despite decreasing HDL-C by >80%, effectively maintained macrophage RCT. In SR-BI knockout mice, probucol also substantially reduced HDL-C but significantly increased macrophage RCT. Furthermore, probucol significantly enhanced the excretion of HDL-derived cholesterol into feces in both WT and SR-BI knockout mice. Probucol inhibited ABCA1-dependent cholesterol efflux from mouse primary hepatocytes, and this effect was shown to be responsible for the effect of probucol on increasing the fecal excretion of HDL-derived cholesterol in vivo. We demonstrate that pharmacological inhibition of hepatic ABCA1 activity with probucol reduced HDL-C levels but promoted RCT through diversion of HDL-derived cholesterol from efflux back into plasma instead to excretion in the bile. These results explain the beneficial effects of probucol on atherosclerosis and xanthomas despite its HDL-lowering effects and suggest that inactivation of hepatic ABCA1 leads to increased RCT despite reducing plasma HDL-C levels.

Lower endothelial progenitor cell number, family history of cardiovascular disease and reduced HDL-cholesterol levels are associated with shorter leukocyte telomere length in healthy young adults

Background and aimsLeukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. Methods and resultsLTL was determined in 82 healthy subjects (49M/33F; age37 ± 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples.LTL resulted inversely correlated with family history of CVD (t = 2.70; p = 0.009), age (r = −0.238; p = 0.032), waist circumference (r = −0.256; p = 0.02), triglycerides (r = −0.218; p = 0.049), PAI-1 (r = −0.288; p = 0.009) and directly correlated with HDL-cholesterol (r = 0.316; p = 0.004) and EPC number (r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD (p = 0.013), EPC count (p = 0.003), and HDL-cholesterol (p = 0.017) were independently associated with LTL (r = 0.62). ConclusionLTL is independently associated to CV risk factors also in healthy young adults.

Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.

Serum Levels of Advanced Glycation End Products (AGEs) are Inversely Associated with the Number and Migratory Activity of Circulating Endothelial Progenitor Cells in Apparently Healthy Subjects

Endothelial progenitor cells (EPCs) have been shown to participate in the process of vascular repair, thus playing a protective role against cardiovascular disease (CVD). It is known that atherosclerotic risk factors could affect EPC number and function. Advanced glycation end products (AGEs) contribute to the pathogenesis of atherosclerosis as well. However, as far as we know, there is no report to show the relationship between serum AGE levels and circulating EPCs in humans. Therefore, in this study, we investigated whether serum level of AGEs was associated with EPC number and functions in apparently healthy subjects, independent of traditional cardiovascular risk factors. Apparently healthy volunteers (34.6 ± 6.9 years old, 40 males and 8 females) who were not on any medications underwent a complete history and physical examination, determination of blood chemistries, including AGEs, and number, differentiation and migratory activity of circulating EPCs. Serum AGEs levels were 9.20 ± 1.85 U/mL. Multiple stepwise regression analysis revealed that serum levels of AGEs and smoking were independently correlated with reduced number of EPCs. Further, female, AGEs, and reduced HDL-cholesterol levels were independently associated with impaired migratory activity of circulating EPCs. This study demonstrated for the first time that the serum level of AGEs was one of the independent correlates of decreased cell number and impaired migratory activity of circulating EPCs in apparently healthy subjects. Our present observations suggest that even in young healthy subjects, serum level of AGEs may be a biomarker that could predict the progression of atherosclerosis and future cardiovascular events.

Vitamin D and cardiovascular disease risk in children

According to a large epidemiologic study, a majority of American children are vitamin D insufficient or deficient. In addition to negative effects on bone metabolism, low vitamin D levels in the pediatric population are associated with adverse cardiovascular risk factors, including an increase in systolic blood pressure and a reduction in HDL cholesterol levels.

Expression of Human ApoAII in Transgenic Rabbits Leads to Dyslipidemia

Apolipoprotein AII (apoAII) is the second major apolipoprotein in high-density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were approximately 30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins. Furthermore, postheparin lipoprotein lipase activity significantly decreased in Tg rabbits compared with non-Tg rabbits. These results indicate that apoAII plays an important role in both VLDL and HDL metabolism, possibly through the inhibition of lipoprotein lipase activity. ApoAII Tg rabbits may become a new model for the study of human familial combined hyperlipidemia.

The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis

Reverse cholesterol transport (RCT) is a term used to describe the efflux of excess cellular cholesterol from peripheral tissues and its return to the liver for excretion in the bile and ultimately the feces. It is believed to be a critical mechanism by which HDL exert a protective effect on the development of atherosclerosis. In this paradigm, cholesterol is effluxed from arterial macrophages to extracellular HDL-based acceptors through the action of transporters such as ABCA1 and ABCG1. After efflux to HDL, cholesterol may be esterified in the plasma by the enzyme lecithin:cholesterol acyltransferase and is ultimately transported from HDL to the liver, either directly via the scavenger receptor BI or after transfer to apolipoprotein B-containing lipoproteins by the cholesteryl ester transfer protein. Methods for assessing the integrated rate of macrophage RCT in animals have provided insights into the molecular regulation of the process and suggest that the dynamic rate of macrophage RCT is more strongly associated with atherosclerosis than the steady-state plasma concentration of HDL cholesterol. Promotion of macrophage RCT is a potential therapeutic approach to preventing or regressing atherosclerotic vascular disease, but robust measures of RCT in humans will be needed in order to confidently advance RCT-promoting therapies in clinical development.

Role of Endothelial Lipase in Plasma HDL levels in a Murine Model of Hypertriglyceridemia

Hypertriglyceridemia is the most common cause of low plasma high-density lipoprotein cholesterol (HDL-C) levels; however, the correlation between high triglyceride (TG) and low HDL-C remains unclear. Endothelial lipase (EL) is a determinant of plasma HDL levels. We investigated the role of EL in HDL metabolism in a murine model of acute hypertriglyceridemia. To establish TG-dominant hyperlipidemia, EL-/- and wild-type (WT) mice were injected with Poloxamer-407 (P-407, 0.5 g/kg, i.p.). A single injection of P-407 resulted in a marked increase in plasma TG and cholesterol levels together with a decrease in HDL-C levels. Although plasma TG levels were similar in EL-/- and WT mice after P-407 injection, HDL-C levels were 80% higher and the HDL particle size was significantly larger in EL-/- mice than in WT mice. P-407 treatment inhibited plasma lipoprotein lipase activity and EL phospholipase activity, without decreasing their expressions. Adenovirus-mediated overexpression of EL in the liver reduced plasma HDL-C levels in both normo- and hyperlipidemic mice, while overexpression of catalytically inactive EL reduced HDL-C levels in hyperlipidemic mice. Cell culture experiments revealed that both catalytically active and inactive EL promoted cellular HDL uptake to the same extent. EL regulates plasma HDL levels in mice in the normolipidemic as well as the acute hypertriglyceridemic state. EL can modulate plasma HDL-CHOL levels through both its lipolytic and ligand-binding functions in hypertriglyceridemic mice, while lipolytic activity appears to be the main determinant for its effects on HDL metabolism in normolipidemic mice.

HDL Remodeling During the Acute Phase Response

The purpose of this study was to examine the interactive action of serum amyloid A (SAA), group IIA secretory phospholipase A(2) (sPLA(2)-IIA), and cholesteryl ester transfer protein (CETP) on HDL remodeling and cholesterol efflux during the acute phase (AP) response elicited in humans after cardiac surgery. Plasma was collected from patients before (pre-AP), 24 hours after (AP-1 d), and 5 days after cardiac surgery (AP-5 d). SAA levels were increased 16-fold in AP-1 d samples. The activity of sPLA(2)-IIA was increased from 77.7+/-38.3 U/mL (pre-AP) to 281.4+/-57.1 U/mL (AP-1 d; P<0.001). CETP mass and activity reduction was commensurate to the reduction of HDL cholesterol levels. The combined action of SAA, sPLA(2)-IIA, and CETP in vitro markedly remodeled HDL with the generation of lipid-poor apoA-I from both pre-AP and AP-1 d HDL. The net result of this remodeling was a relative preservation of ABCA1- and ABCG1-dependent cholesterol efflux during the acute phase response. Our results show that the many and complex changes in plasma proteins during the acute phase response markedly remodel HDL with functional implications, particularly the relative retention of cholesterol efflux capacity.