Cholesterol In Peripheral Tissues Research Articles

ATP‐binding cassette transporter 1 (ABCA1) deficiency decreases platelet reactivity and reduces thromboxane A2 production independently of hematopoietic ABCA1

ESSENTIALS: The role of ATP-binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1-deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1. The ATP-binding cassette transporter ABCA1 is required for the conversion of apolipoprotein A-1 to high-density lipoprotein (HDL), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA1 in platelet functions remains poorly characterized. To determine the role of ABCA1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA1-deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium-induced phosphatidylserine exposure. Interestingly, ABCA1-deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 (TXA2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA2, was primarily dependent on external environment and not on the hematopoietic ABCA1. Decreased aggregation and production of TXA2 and eicosanoids were also observed in platelets from Tangier patients. Absence of ABCA1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA2 production through a hematopoietic ABCA1-independent mechanism.

The role of the lymphatic system in cholesterol transport.

Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.

Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia. Cross-sectional study in all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014. Deleteriousness and nondeleteriousness of familial hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene (APOB) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. Prevalence of type 2 diabetes. The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25,137) vs 2.93% in unaffected relatives (n = 1119/38,183) (P < .001; odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted prevalence of type 2 diabetes in familial hypercholesterolemia, determined using multivariable regression models, was 1.44% (difference, 1.49% [95% CI, 1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P < .001). The adjusted prevalence of type 2 diabetes by APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively (P for trend <.001 in both comparisons). In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.

Abstract 5299: Evaluation of apolipoprotein E polymorphism on the aggressive potential of prostate cancer cell lines.

Abstract Introduction: Defective cholesterol-modulating apolipoprotein E (ApoE) isoforms could exacerbate prostatic neoplasia. Recent evidence strongly suggests that specific genetic variants of ApoE control peripheral tissue cholesterol efflux. Defects in ApoE may result in reduced prostate cancer cell cholesterol efflux and enriched concentrations of cholesterol in membranes by reducing clearance. Membrane-rich cholesterol could potentially activate cancer-driven signaling processes. Objective: To determine the relevance of specific ApoE phenotypes as risk factors of aggressive prostate cancer based on their influence on reverse cholesterol transport. Methods: We evaluated ApoE genotypes of the weakly tumorigenic or nonaggressive prostate cancer cell lines (LNCaP and MDA PCA 2b), and the moderate and highly tumorigenic or aggressive prostate cancer cell lines (PC-3 and DU-145). We examined whether ApoE2/E4 variants were associated with tumor aggressiveness via the expression of caveolin-1(cav-1), a cholesterol-regulated pro-carcinogenic gene. Results: We observed that the nonaggressive prostate cancer cell lines carried either the Apo ε3/ε3 or ε3/ε4 alleles, while the aggressive prostate cancer cell lines carried the Apo ε2/ε4 alleles. Our results showed a two-fold increase in the expression of cav-1 in the aggressive cell lines, as opposed to the nonaggressive ones. There was a significantly (p&amp;lt;0.01) greater cholesterol efflux from the nonaggressive cells lines compared to the aggressive cells. Also, the aggressive cell lines retained and localized more cholesterol in their membranes as opposed to the less aggressive cell lines. Conclusions: These results suggest an association between cholesterol status and the aggressive potential of prostate cancer cells. It also highlights the need for further investigation into whether ApoE2/E4 is the dysfunctional phenotype, and whether it has the potential as a biomarker of aggressive prostate cancer. GRANT SUPPORT: NIH R25CA047888 Citation Format: Godwin O. Ifere, Wendy Demark-Wahnefried, Renee Desmond, Tim R. Nagy. Evaluation of apolipoprotein E polymorphism on the aggressive potential of prostate cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5299. doi:10.1158/1538-7445.AM2013-5299

Role of Phospholipid Transfer Protein in High-Density Lipoprotein– Mediated Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) describes the process whereby cholesterol in peripheral tissues is transported to the liver where it is ultimately excreted in the form of bile. Given the atherogenic role of cholesterol accumulation within the vessel intima, removal of cholesterol through RCT is considered an anti-atherogenic process. The major constituents of RCT include cell membrane– bound lipid transporters, plasma lipid acceptors, plasma proteins and enzymes, and lipid receptors of liver cell membrane. One major cholesterol acceptor in RCT is high-density lipoprotein (HDL). Both the characteristics and level of HDL are critical determinants for RCT. It is known that phospholipid transfer protein (PLTP) impacts both HDL cholesterol level and biological quality of the HDL molecule. Recent data suggest that PLTP has a site-specific variation in its function. Moreover, the RCT pathway also has multiple steps both in the peripheral tissues and circulation. Therefore, PLTP may influence the RCT pathway at multiple levels. In this review, we focus on the potential role of PLTP in RCT through its impact on HDL homeostasis. The relationship between PLTP and RCT is expected to be an important area in finding novel therapies for atherosclerosis.

Structure of Apolipoprotein A-I N Terminus on Nascent High Density Lipoproteins

Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and a critical element of cholesterol metabolism. To better elucidate the role of the apoA-I structure-function in cholesterol metabolism, the conformation of the apoA-I N terminus (residues 6-98) on nascent HDL was examined by electron paramagnetic resonance (EPR) spectroscopic analysis. A series of 93 apoA-I variants bearing single nitroxide spin label at positions 6-98 was reconstituted onto 9.6-nm HDL particles (rHDL). These particles were subjected to EPR spectral analysis, measuring regional flexibility and side chain solvent accessibility. Secondary structure was elucidated from side-chain mobility and molecular accessibility, wherein two major α-helical domains were localized to residues 6-34 and 50-98. We identified an unstructured segment (residues 35-39) and a β-strand (residues 40-49) between the two helices. Residues 14, 19, 34, 37, 41, and 58 were examined by EPR on 7.8, 8.4, and 9.6 nm rHDL to assess the effect of particle size on the N-terminal structure. Residues 14, 19, and 58 showed no significant rHDL size-dependent spectral or accessibility differences, whereas residues 34, 37, and 41 displayed moderate spectral changes along with substantial rHDL size-dependent differences in molecular accessibility. We have elucidated the secondary structure of the N-terminal domain of apoA-I on 9.6 nm rHDL (residues 6-98) and identified residues in this region that are affected by particle size. We conclude that the inter-helical segment (residues 35-49) plays a role in the adaptation of apoA-I to the particle size of HDL.

High-Density Lipoprotein: Key Molecule in Cholesterol Efflux and the Prevention of Atherosclerosis

Accumulation of cholesterol by macrophages, leading to their transformation into foam cells is a key event in the initiation of atherosclerosis. As maintenance of cholesterol homeostasis in macrophages is essential to prevent foam cell formation, mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years. Several epidemiological studies have shown that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis. The protective effect of HDL against macrophage foam cell formation and atherosclerosis is primarily attributed to its role in reverse cholesterol transport (RCT), a process by which excess cholesterol in peripheral tissues is transported to the liver for excretion. The present review discusses current knowledge on the biological activities of the major apolipoproteins, enzymes, lipid transfer proteins, receptors, and lipid transporters associated with HDL function and levels. In addition, current views on the molecular mechanisms underlying the atheroprotective functions of HDL beyond promotion of RCT, including the anti-oxidant, anti-thrombotic, anti-inflammatory and anti-apoptotic properties of HDL are summarized.

Apolipoprotein M expression increases the size of nascent preβ HDL formed by ATP binding cassette transporter A1

Apolipoprotein M (apoM) is a novel apolipoprotein that is reportedly necessary for pre beta HDL formation; however, its detailed function remains unknown. We investigated the biogenesis and properties of apoM and its effects on the initial steps of nascent pre beta HDL assembly by ABCA1 in HEK293 cells. Transiently transfected apoM was localized primarily in the endomembrane compartment. Pulse-chase analyses demonstrated that apoM is inefficiently secreted, relative to human serum albumin, and that approximately 50% remains membrane-associated after extraction with sodium carbonate, pH 11.5. To investigate the role of apoM in nascent pre beta HDL formation, ABCA1-expressing or control cells, transfected with empty vector, apoM, or C-terminal epitope-tagged apoM (apoM-C-FLAG), were incubated with (125)I-apoA-I for 24 h. Conditioned media were harvested and fractionated by fast-protein liquid chromatography (FPLC) to monitor HDL particle size. Pre beta HDL particles were formed effectively in the absence of apoM expression; however, increased apoM expression stimulated the formation of larger-sized nascent pre beta HDLs. Immunoprecipitation with anti-apoA-I antibody followed by apoM Western blot analysis revealed that little secreted apoM was physically associated with pre beta HDL. Our results suggest that apoM is an atypical secretory protein that is not necessary for ABCA1-dependent pre beta HDL formation but does stimulate the formation of larger-sized pre beta HDL. We propose that apoM may function catalytically at an intracellular site to transfer lipid onto pre beta HDL during or after their formation by ABCA1.

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.

Serum Opacity Factor Unmasks Human Plasma High-Density Lipoprotein Instability via Selective Delipidation and Apolipoprotein A-I Desorption

Human plasma high-density lipoproteins (HDL) are important vehicles in reverse cholesterol transport, the cardioprotective mechanism by which peripheral tissue-cholesterol is transported to the liver for disposal. HDL is the target of serum opacity factor (SOF), a substance produced by Streptococcus pyogenes that turns mammalian serum cloudy. Using a recombinant (r) SOF, we studied opacification and its mechanism. rSOF catalyzes the partial disproportionation of HDL into a cholesteryl ester-rich microemulsion (CERM) and a new HDL-like particle, neo HDL, with the concomitant release of lipid-free (LF)-apo A-I. Opacification is unique; rSOF transfers apo E and nearly all neutral lipids of approximately 100,000 HDL particles into a single large CERM whose size increases with HDL-CE content (r approximately 100-250 nm) leaving a neo HDL that is enriched in PL (41%) and protein (48%), especially apo A-II. rSOF is potent; within 30 min at 37 degrees C, 10 nM rSOF opacifies 4 microM HDL. At respective low and high physiological HDL concentrations, LF-apo A-I is monomeric and tetrameric. CERM formation and apo A-I release have similar kinetics suggesting parallel or rapid sequential steps. According to the reaction products and kinetics, rSOF is a heterodivalent fusogenic protein that uses a docking site to displace apo A-I and bind to exposed CE surfaces on HDL; the resulting rSOF-HDL complex recruits additional HDL with its binding-delipidation site and through multiple fusion steps forms a CERM. rSOF may be a clinically useful and novel modality for improving reverse cholesterol transport. With apo E and a high CE content, CERM could transfer large amounts of cholesterol to the liver for disposal via the LDL receptor; neo HDL is likely a better acceptor of cellular cholesterol than HDL; LF-apo A-I could enhance efflux via the ATP-binding casette transporter ABCA1.

Poloxamer 407 (P-407)-mediated reduction in the gene expression of ATP-binding-cassette transporter A1 may contribute to increased cholesterol in peripheral tissues of P-407-treated rats

The purpose of this study was to determine whether poloxamer 407, a chemical known to increase plasma lipid levels in rodents following parenteral administration, decreased the gene expression of ATP-binding-cassette transporter A1. Using human macrophages cultured with poloxamer 407, there was a significant reduction in the gene expression of ATP-binding-cassette transporter A1; however, there was no effect on the gene expression of either fatty acid synthase or sterol regulatory element binding protein-1. Reduction of ATP-binding-cassette transporter A1 mRNA levels was also observed in both liver and intestine of poloxamer 407-treated rats. When macrophages were cultured with poloxamer 407, the percent of cholesterol effluxed decreased in a concentration-dependent fashion, both in the absence and presence of a synthetic liver X receptor agonist. Lastly, total and unesterified (free) cholesterol concentrations were determined in the liver and 9 peripheral tissues of poloxamer 407- and saline-injected (control) rats. In every tissue, the concentration of total cholesterol for poloxamer 407-treated rats was significantly greater than the corresponding value for controls. Our findings would seem to suggest that the poloxamer 407-mediated reduction in both ATP-binding-cassette transporter A1 gene expression and cellular cholesterol efflux may potentially be one factor that contributes to the accumulation of cholesterol and cholesteryl esters in the liver and 9 peripheral tissues of poloxamer 407-treated rats. Furthermore, the surprising specificity by poloxamer 407 for inhibition of ATP-binding-cassette transporter A1 gene expression over fatty acid synthase and sterol regulatory element binding protein-1 may potentially be due to either disruption of a transcriptional cofactor required for ATP-binding-cassette transporter A1 gene expression, or enhanced turnover of ATP-binding-cassette transporter A1 mRNA.

Reverse cholesterol transport: high-density lipoprotein's magnificent mile.

High-density lipoproteins (HDLs) are among the most structurally complex and functionally versatile forms of circulating serum lipoproteins. HDLs undergo extensive enzymatic remodeling during their maturation in serum, interact with highly specific receptors in peripheral tissues and the liver, and are able to exert a variety of antiatherogenic effects (eg, inhibit inflammation, oxidation, and apoptosis). Considerable epidemiologic, clinical, and basic scientific investigation supports the conclusion that HDLs as a molecular class are atheroprotective. One of the most important antiatherogenic functions of HDL is its capacity to drive reverse cholesterol transport, the process by which excess cholesterol in peripheral tissues is extracted and delivered to the liver for disposal. Despite the rapid expansion in our understanding of how HDL antagonizes many of mechanisms etiologic for atherosclerosis and the observation that a low serum level of HDL is the most frequent lipid abnormality in patients with premature coronary artery disease, many physicians still focus inadequate attention on recognizing and treating hypoalphalipoproteinemia. Our current understanding of reverse cholesterol transport reinforces the clinical importance of including HDL screening when evaluating any given patient’s risk for cardiovascular disease.

Construction and characterization of polycistronic retrovirus vectors for sustained and high-level co-expression of apolipoprotein A-I and lecithin–cholesterol acyltransferase

Apolipoprotein A-I (apo A-I) and lecithin–cholesterol acyltransferase (LCAT) are constituents of circulating high-density lipoprotein (HDL) particles and play an important role in ‘reverse cholesterol transport’, the process by which cholesterol in peripheral tissues is transferred to the liver for excretion. Enhancing levels of apo A-I, as well as LCAT, in plasma may promote the removal of excess cholesterol from the arterial wall and thus reduce the formation of atherosclerotic lesions. Indeed, both apo A-I and LCAT genes have been identified as therapeutic targets to prevent or limit atherogenesis. Here, we have constructed two retroviral vectors, one containing LCAT cDNA and the neomycin phosphotransferase (NEO) gene (pLLEN), the other apo A-I cDNA, LCAT cDNA and the NEO gene (pLAPLEN) linked by internal ribosome entry sites (IRES). Both bi- and tricistronic retroviral vectors efficiently co-expressed their two or three genes when transfected into cultured mouse C2C12 muscle cells or human 293 cells. After 30 days, the retroviral vector sequences were retained by the host cells, whereas those of a conventional plasmid vector were lost. Moreover, transduced C2C12 mouse myoblasts maintained the ability for heterologous expression of human LCAT and apo A-I even after differentiation into myotubes. Stably-transduced clones of C2C12 cells were selected by neomycin (G418) resistance and continued to efficiently express human LCAT for 60 days. These findings indicate that the use of polycistronic retrovirus vectors to genetically modify myoblasts, which can be transplanted back into skeletal muscle, might be a safe and feasible strategy to express human apo A-I and LCAT and hence have therapeutic potential to regress atherosclerotic lesions.

In vivo cholesterol kinetics in apolipoprotein E-deficient and control mice.

The in vivo total body cholesterol transport of homozygous apoE-deficient (-/-) and control (+/+) mice was evaluated by compartmental analysis of plasma cholesterol decay. Body cholesterol fractional catabolic rates of chow fed mutants were less (-/-, 0.17 +/- 0.02; +/+, 0.51 +/- 0.06 day-1) and body cholesterol contents greater (-/-, 68 +/- 5; +/+, 48 +/- 5 mumol) than controls. The body cholesterol expansion of the chow-fed mutant was extracellular with at least half in plasma. Cholesterol transport, i.e., the mass entering, moving through, and exiting the body each day, was similar (-/-, 6.9 +/- 0.7; +/+, 8.5 +/- 0.9 mumol/day) for homozygotes and controls on chow, and both tripled with cholesterol feeding. Differing from controls, however, mutants had considerable expansions of plasma and body cholesterol (-/-, 166 +/- 21; +/+, 59 +/- 11 mumol) with increments in peripheral tissue cholesterol contents. Cholesterol feeding increased control hepatic cholesterol without a change in plasma, whereas mutants had large increments in plasma cholesterol with no change in liver. Consistent with impaired hepatic uptake of cholesterol, mutants had much slower plasma clearance of lipoprotein cholesterol, as well as slower transfer to catabolic pools than normals. Treatment of homozygotes with lovastatin doubled both plasma cholesterol concentration and body cholesterol transport indicating the importance of apoE-dependent cell cholesterol transfer in synthetic down-regulation with this agent. These data indicate that mice lacking apoE have lower affinity hepatic uptake of plasma remnant cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary regulation of maternal and fetal cholesterol metabolism in the guinea pig

Studies to determine the effects of pre-natal interventions on maternal and fetal cholesterol homeostasis were carried out in the guinea pig. Guinea pig dams were fed either non-purified guinea pig diet or diet supplemented with either 1.1% of the bile acid binding resin cholestyramine or 0.25% cholesterol. Whole body rates of endogenous cholesterol synthesis were determined by quantitation of [3H]water incorporation into digitonin precipitable sterols in non-pregnant animals and at 40 and 60 days of gestation in the dam and fetus. Maternal hepatic cholesterol synthesis was reduced 87% by dietary cholesterol and was increased 3.5-fold with cholestyramine feeding. Fetal hepatic and peripheral tissue cholesterol synthesis rates peaked at 40 days gestation when peripheral tissue cholesterol synthesis was 5.7-fold higher and hepatic synthesis 6.2-fold greater than the near adult levels observed at 60 days. Cholesterol synthesis in the fetus was relatively insensitive to dietary manipulations; however, maternal cholestyramine treatment did result in a 1.4-fold increase in fetal carcass cholesterol synthesis at 60 days gestation. These data demonstrate that maternal cholesterogenic systems maintain responsiveness to dietary regulation during pregnancy; whereas fetal cholesterol homeostasis is relatively insensitive to dietary cholesterol throughout gestation yet may respond to induction by maternal cholestyramine treatment during the late gestation period.

Copper and copper-nicotinic acid complexes mediated oxidation of high density lipoprotein.

Plasma high density lipoprotein (HDL)-cholesterol and/or apo A-I levels appear to be inversely related to the occurrence of acute myocardial infarctions and have an impact on the onset and progress of atherosclerosis.1,2 Since the outer surface of the high density lipoprotein particle has a low cholesterol/phosphatidylcholine ratio in comparison to most of the cell membranes,3 it is suggested to be an effective acceptor for the transport of cholesterol to various tissues. HDL facilitates the removal of the peripheral tissue cholesterol and delivers it within the “reverse cholesterol transport” to the liver.4 A recent investigation5 on the scavenger function of sinusoidal liver cells showed that chemically acetylated HDL underwent receptor-mediated endocytosis through a pathway distinct from acetylated low-density lipoprotein (LDL) or formaldehyde-treated serum albumin, which suggests the presence of a scavenger receptor for acetylated HDL.

Influence of age and sex on composition and lipid fluidity in miniature swine plasma lipoproteins

Age- and sex-related differences were observed in the plasma cholesterol level, the plasma concentrations of certain lipoprotein components, and the HDL lipid phase fluidity in miniature swine from post-weaning (6 weeks) through puberty (6 months), maturity (2–6 years), and old age (10–12 years). Age effects were more dominant in the males, with VLDL protein; LDL protein, triacylglycerol, and phospholipid; and HDL triacylglycerol, phospholipid, cholesterol, and polyunsaturated fatty acids showing statistically significant negative correlations with age. These effects were not observed in females. HDL cholesterol was positively correlated with age in females. Total plasma cholesterol decreased with age in males only, but plasma triacylglycerol was not influenced by age in either sex. Higher concentrations of all lipoprotein lipids were observed in the female minipigs regardless of age. HDL lipids became less fluid with age in the males alone suggesting a physical chemical basis for the lower incidence of heart disease among females. The more fluid HDL circulating in the female may be more capable of mobilizing peripheral tissue cholesterol for catabolism thus protecting her from developing atherosclerotic lesions.

Physical exercise and the prevention of atherosclerosis and cholesterol gall stones

Summary There is accumulating evidence in man and experimental animals that even mild exercise, if regularly repeated, may alter the metabolism of lipids. Exercise has been reported as decreasing peripheral tissue cholesterol in red blood cells, working muscle, lungs and the liver. During physical activity, the output of cholesterol and bile acids into the bile increases. This probably leads to higher faecal losses of sterols which may lead to lower cholesterol levels in the peripheral tissues and in the bile, when exercise is repeated regularly. Preferential release of unsaturated fatty acids from the adipose tissue during exercise and the linoleic acid-dependent LCAT enzyme (transporting plasma cholesterol) may be partly responsible for this effect of exercise. The experimental data reviewed provide supportive basis for epidemiological studies reporting on the beneficial effect of regular exercise. Physical activity is an important factor in the phylogeny of all animal species, secondary only to food intake and reproduction. Exercise is readily available to all population groups. There is good evidence that the amount of exercise required for a protective effect is easily accessible for time-pressured and older individuals. Short bursts of activity repeated several times a day may be equally or more beneficial than prolonged exhaustive exercise. Modified exercise is also beneficial for patients with coronary heart disease and for elderly patients, provided this is done under strict medical supervision. To be effective, physical exercise should be regular and continuous throughout life.