Role Of High-density Lipoprotein Research Articles

AS-195: Role of High-Density Lipoprotein and Coronary Artery Endothelial Dysfunction

AS-195: Role of High-Density Lipoprotein and Coronary Artery Endothelial Dysfunction

HDL, lipid peroxidation, and atherosclerosis

Genetic, clinical, and pharmacological studies implicate elevated levels of LDL in the pathogenesis of atherosclerotic vascular disease, the leading cause of death in industrialized societies (1). Paradoxically, native LDL fails to exert potentially atherogenic effects in vitro, suggesting that it must be modified to promote vascular disease. Indeed, many lines of evidence support the LDL oxidation hypothesis, which suggests that oxidative damage to LDL is one important mechanism for rendering lipoproteins atherogenic (as reviewed in Refs. 2, 3).

High-density lipoproteins: the guardian angel of the cell membrane

High-density lipoproteins (HDL) plasma levels are inversely correlated with the risk of atherosclerosis and coronary heart disease. The protective effect of HDL has been related to their role in the cholesterol reverse transport and to their ability to inhibit oxidation of low-density lipoproteins (LDL). Several lines of evidence suggest that the protective effect of HDL is at least partially related to the enzyme paraoxonase (PON1), a calcium-dependent esterase associated with the HDL surface. It has been hypothesised that PON1 may have two independent antiatherogenic roles: (a) by preventing the accumulation of oxidised lipids from oxidised lipoproteins (LDL and HDL) and thereby inhibiting the atherogenic and inflammatory response induced by lipid peroxidation products; (b) by detoxifying homocysteine thiolactone (HTL), a toxic metabolite of homocysteine. Recently, it has been reported that HDL-associated PON1 could also play a regulatory role in HDL binding to cell membranes and in HDL-mediated cholesterol efflux in macrophages. Several papers have reported that HDL are also able to protect and/or repair oxidative damage of cell membranes and we have recently demonstrated that the protective role of HDL is related to PON1 activity.

Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux

Among the known mechanisms of reverse cholesterol transport (RCT), ATP binding cassette transporter G1 (ABCG1)-mediated free cholesterol (FC) transport is the most recent and least studied. Here, we have characterized the efficiencies of different acceptors using baby hamster kidney (BHK) cells transfected with human ABCG1 cDNA, which is inducible upon treatment with mifepristone. When normalized on particle number and particle surface area, the acceptor efficiency for FC efflux was as follows: small unilamellar vesicles (SUV)>LDL>reconstituted HDL>HDL2 = HDL3. Based on phospholipid content, the order was reversed. ABCG1 also mediated phospholipid efflux to human serum and HDL3. ABCG1-mediated FC efflux correlated significantly with a number of HDL subfractions and components in serum collected from 25 normolipidemic individuals: apolipoprotein A-II (apoA-II) (r2 = 0.7), apolipoprotein A-I (apoA-I) (r2 = 0.5), HDL-C (r2 = 0.4), HDL-PL (r2 = 0.4), α-2 HDL (r2 = 0.4), and preβ HDL (r2 = 0.2). ABCG1 did not enhance influx of FC or cholesteryl oleyl ether (COE) when cells were incubated with radiolabeled HDL3. ABCG1 expression did not increase the association of HDL3 with cells. Compared with control cells, ABCG1 expression significantly increased the FC pool available for efflux and the rate constant for efflux. In conclusion, composition and particle size determine the acceptor efficiency for ABCG1-mediated efflux. ABCG1 increases cell membrane FC pools and changes its rate of desorption into the aqueous phase without enhancing the association with the acceptor.

I405V and TaqIB polymorphisms of the cholesteryl ester transfer protein and their relation to serum lipid and lipoprotein levels in a Turkish population

Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Genetic polymorphisms of the CETP gene can influence levels of serum lipoproteins. It has been reported that mean HDL-cholesterol (HDL-C) concentrations are low in Turkish population. Thus, we investigated the frequencies of the common I405V and TaqIB polymorphisms of the CETP gene and their relation to serum lipid and lipoprotein levels in a Turkish population. The variant allele frequencies of I405V and TaqIB polymorphisms of the CETP gene were found to be 0.38 and 0.46, respectively and similar to some of the European populations. Subjects for the VV genotype of I405V polymorphism had higher HDL-C levels than did II subjects. The covariance analysis showed that gender and triglyceride (TG) levels have an effect on the association of HDL-C and I405V polymorphism. In conclusion, our results indicate that I405V polymorphism may affect the HDL-C levels in Turkish population. The association of this polymorphism and HDL-C levels could be modified by other factors, such as gender and TG levels.

Multiple actions of high-density lipoprotein

Purpose of review The most accepted property of high-density lipoprotein is reverse cholesterol transport. However, other beneficial actions may contribute to the antiatherogenic role of high-density lipoprotein. This review addresses the action of high-density lipoprotein beyond reverse cholesterol transport. Recent findings High-density lipoprotein cholesterol levels are inversely associated with coronary heart disease and other forms of vascular disease. Apart from transferring excess cholesterol to the liver, high-density lipoprotein exhibits favorable effects on oxidation, inflammation, thrombosis and endothelial function. Some of these actions are at least in part attributed to high-density lipoprotein-associated enzymes, such as paraoxonase and platelet-activating factor acetylhydrolase. However, high-density lipoprotein can become dysfunctional and proatherogenic under certain circumstances. Summary Current data suggest that high-density lipoprotein possesses various properties beyond reverse cholesterol transport. However, many issues on the exact role of high-density lipoprotein remain unknown. Future research is needed.

Coronary Artery Diseases in South Asian Immigrants: An Update on High Density Lipoprotein Role in Disease Prevention

Over the past several years, the overall prevalence and incidence of cardiovascular diseases (CVD) including coronary artery diseases (CAD) have declined in the United States (US) and in many developed countries. However, among South Asian in general and South Asian immigrants (SAIs) in particular, a disturbing trend toward high rates of CAD has been noted. This trend is associated with a high prevalence of conventional risk factors and metabolic syndrome in this population, yet these conventional risk factors may not account for the greater CAD risk among SAIs. A search for additional markers is warranted, to enable early detection and prevention of CAD in this high risk group. High density lipoprotein (HDL) is one of the predictor of CAD and is considered to be cardio-protective. However, some of the recent studies have shown that HDL is not only ineffective as an antioxidant but, paradoxically, appears to be pro-oxidant, and has been found to be associated with CAD. Such HDL is called dysfunctional HDL. We present here an overview CAD and CAD risk factors in general and dyslipidemias in particular in SAIs. In addition, the evolving theories on dysfunctional HDL and its impact on CAD are also briefly presented.

The protective role of high‐density lipoprotein on LPS‐induced acute lung injury on mice

The protective role of high‐density lipoprotein on LPS‐induced acute lung injury on mice

Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis

The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, −629C/A, Taq1B, and −2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p < 0.001) and activity (13.1% and 9.4%, respectively; p < 0.01) and lower HDL-C (5.6% and 6.0%, respectively; p < 0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C ( p = 0.006 and p = 0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque ( p = 0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the −629A, Taq1B B2, and −2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p < 0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p < 0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p < 0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.

HDL metabolism and the role of HDL in the treatment of high-risk patients with cardiovascular disease

Developing new therapeutic approaches to treating residual cardiovascular risk of recurrent clinical events in statin-treated patients has been a major challenge for the cardiovascular field. Data from epidemiological evidence, animal models, and initial clinical trials indicate that increasing high-density lipoprotein (HDL) may be an effective new target for treating residual cardiovascular risk. Over the past several years, major advances have occurred in our understanding of HDL metabolism and of the important roles of the ABCA1 and ABCG1 transporters as well as the SR-BI receptor in cholesterol transport. Current approaches to HDL therapy include acute HDL infusion therapy in acute coronary syndrome patients and chronic oral HDL therapy in stable patients with cardiovascular disease. Definitive clinical trials will now be required to establish the safety and efficacy of increasing HDL in the treatment of patients with cardiovascular disease.

New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease

Several known functions of high-density lipoproteins (HDLs) may contribute to their ability to protect against atherosclerosis. The best known of these functions is the ability to promote cholesterol efflux from cells in a process that may minimize the accumulation of foam cells in the artery wall. However, HDLs have additional properties, including antioxidant, anti-inflammatory, and antithrombotic effects, that may also be anti-atherogenic. Recent in vivo studies in several animal models have demonstrated that HDLs can inhibit acute and chronic vascular inflammation. The fact that these effects can be achieved with very low doses of reconstituted discoidal HDL or even lipid-free apolipoprotein A-I suggests that they may reflect activity of a minor, highly active HDL subpopulation. These results have potentially important clinical implications in regard to managing the acute vascular inflammation states that accompany acute coronary syndrome and acute ischemic stroke.

Abstract 1392: Increased High Density Lipoprotein Cholesterol induced by Human Apolipoprotein A-I Gene Transfer increases Adiponectin Expression in abdominal Adipose Tissue

Introduction: High density lipoprotein (HDL) cholesterol (C) levels positively correlate with plasma adiponectin levels. However, the role of HDL on adiponectin expression is unkown. To investigate the effect of increased HDL levels on adiponectin expression, 1) gene transfer with human apolipoprotein (apo) A-I, the main apo of HDL, was performed in control mice and in lipopolysaccharide (LPS)-injected mice, associated with decreased adiponectin levels and 2) HDL was supplemented in vitro on (pre)-adipocytes. Methods: Eight weeks old male C57BL/6 mice were i.v. injected with 5 × 10e10 total particles of the E1E3E4-deleted adenoviral vector Ad.hapoA-I, expressing human apo A-I or with the same dose of Ad.Null, containing no expression cassette. Fourteen days hereafter, mice were i.p. injected with LPS from Escherichia coli at a dose of 80 mg/kg or with saline. Mice were sacrificed 12 hours after LPS or saline injection. Human apo A-I and mouse adiponectin plasma concentrations were determined by ELISA. Abdominal fat phospho (p) and total (tot.) Akt protein levels were determined by Western Blot; adiponectin mRNA expression of (pre)-adipocytes by real-time PCR. Results: Ad.hapoA-I GT resulted in human apo A-I expression levels of 83Â27&gt;4.6 mg/dl at day 14, which was associated with 1.8-fold (p&lt;0.05) and 1.5-fold (p&lt;0.05) higher HDL-C and adiponectin levels compared to Ad.Null mice, respectively. After LPS-injection, human apo A-I levels decreased by 1.7-fold (p&lt;0.001), leading to 1.7-fold lower adiponectin levels compared to Ad.hapoA-I control mice, but still 1.5-fold (p&lt;0.01) higher compared to LPS-Ad.Null mice. The increased adiponectin levels in Ad.hapoA-I versus Ad.Null LPS-injected mice were associated with a 1.7-fold (p&lt;0.05) increase in p-Akt/tot.Akt ratio. In vitro, LPS administration decreased adiponectin expression by 2.1-fold (p&lt;0.01), which was normalized to control levels by HDL supplementation in a phosphatidylinositol-3-kinase (PI3K)-dependent manner, since Ly 294002 reversed the HDL-mediated increase in adiponectin expression. Conclusion: HDL increases adiponectin expression via the PI3K-Akt pathway, which may contribute to some of the pleiotropic actions of HDL such as its well-known anti-inflammatory effects.

Abstract 1525: High Density Lipoprotein Cholesterol is Protective Against the Development of Cardiac Rhythm Disturbances in the Non-ST Segment Elevation Acute Coronary Syndrome

INTRODUCTION: Many studies have demonstrated that reduced high-density lipoproteins (HDL) levels and elevated triglyceride (TG)/HDL ratio correlate with the development of chronic ischemic heart disease. The role of HDL and the development of cardiac rhythm disturbances in the non-ST segment elevation acute coronary syndrome (ACS) is unclear. HYPOTHESIS: We assessed the hypothesis that HDL might be protective against development of cardiac rhythm disturbances. Additionally, any protective effect was compared with TG/HDL and LDL/HDL in this setting. METHODS: A total of 6881 patients who presented during 2000–2003 with non-ST segment elevation ACS had fasting lipid panels collected within the first 24 hours of admission. Patients were followed for the development of rhythm disturbances of up to 6 years after initial presentation, with a mean of 1269 days. These patients were further separated into diabetic and nondiabetic groups. RESULTS: After adjustment for ischemic heart disease, congestive heart failure, stroke, peripheral vascular disease, hypertension, low density lipoprotein cholesterol, triglycerides, age, and body mass index, higher HDL levels were found to be independently protective against developing atrial fibrillation and other cardiac rhythm disturbances. TG/HDL and LDL/HDL were also protective of cardiac arrhythmias but not with the same power as low HDL (HDL &gt; 31mg/dl, HR = 3.69, 95% CI=3.01– 4.53, P &lt; 0.05). CONCLUSIONS: Based on the above results, patients with lower HDL levels during hospitalizations with non-ST segment elevation ACS have a greater chance of developing cardiac rhythm disturbances independent of other risk factors. Although higher TG/HDL and LDL/HDL are also predictive, lower HDL is associated with highest OR for the development of cardiac arrhythmia among diabetic and non-diabetic patients with non-ST elevation with ACS.

The anti-atherogenic properties of HDL particles

Abstract High density lipoproteins (HDLs) are a class of lipoproteins characterized by small diameter and high density. Epidemiological studies have demonstrated that HDL cholesterol levels are inversely and independently related to the incidence of coronary heart disease. The mechanisms involved in HDL protection against atherosclerosis are uncertain, but the beneficial effect of HDLs might be the consequence of its properties. The best known of them is related to the “reverse cholesterol transport”, i.e. the transfer of cholesterol from non-hepatic cells to the liver. Second, HDLs exert anti-inflammatory activity by inhibiting the expression of adhesion molecules by endothelial cells and the subsequent transmigration of monocytes. Third, HDLs have antioxidant activity through the anti-oxidative properties of apoprotein A-I, and the presence of enzymes such as paraoxonase, glutathione-peroxidase, and PAF acetylhydrolase. Fourth, HDLs display an anti-thrombotic effect by inhibiting platelets aggregation, reducing von Willebrand factor levels, and enhancing the activity of activated protein C and S. Fifth, HDLs have a beneficial effect on endothelial function by activating endothelial NO synthase and enhancing NO release. Finally, high HDL-C has been associated with “longevity syndrome” while low HDL-C has been related to the “frailty syndrome”, suggesting a possible role of HDL in the phenomenon of successful aging.

A role for high density lipoproteins in hepatic phosphatidylcholine homeostasis

Choline is (95%) found largely in the biosphere as a component of phosphatidylcholine (PC) which is made from choline via the CDP-choline pathway. Animals obtain choline from both the diet and via endogenous biosynthesis that involves the conversion of phosphatidylethanolamine into PC by phosphatidylethanolamine N-methyltransferase (PEMT), followed by PC catabolism. We have uncovered a striking gender-specific conservation of choline in female mice that does not occur in male mice. Female Pemt−/− mice maintained hepatic PC/total choline levels during the first day of choline deprivation and escaped liver damage whereas male Pemt−/− mice did not. Plasma PC levels in high-density lipoproteins (HDLs) were higher in male Pemt−/− mice than those in females before choline deprivation. Interestingly, after choline deprivation for 1 day, female, but not male, Pemt−/− mice increased HDL-PC levels. Glybenclamide, an inhibitor of PC efflux mediated by ABC transporters, eliminated this response to choline deprivation in females. These data suggest that (i) increased PC efflux from extra-hepatic tissues to HDLs in the circulation provided sufficient choline for the liver and compensated for loss of hepatic PC during the initial stages of choline deprivation in female, but not male, Pemt−/− mice, and (ii) plasma HDL in female mice has an important function in maintenance of hepatic PC as an acute response to severe choline deprivation.

Phospholipase A1: structure, distribution and function

Phospholipase (PL)A1 is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids. Although PLA1 activities have been detected in many organisms and tissues, their functions have not been elucidated until recently. Currently, six extracellular and three intracellular PLA1 enzymes are known in mammals. The extracellular PLA1s consist of phosphatidylserine (PS)-specific PLA1 (PS-PLA1), membraneassociated phosphatidic acid (PA)-selective PLA1s (mPA-PLA1 and mPA-PLA1 ), hepatic lipase (HL), endothelial lipase (EL) and pancreatic lipas–elated protein (PLRP)-2, all of which belong to the lipase gene family. PS-PLA1, EL, mPA-PLA1 and mPA-PLA1 prefer phospholipid substrates, whereas HL and PLRP-2 show both PLA1 activity and lipase activity to hydrolyze triacylglycerol. EL has a role in high-density lipoprotein (HDL) metabolism by hydrolyzing phosphatidylcholine on HDL particles. PS-PLA1, mPA-PLA1 and mPA-PLA1 have distinct structural features in two surface loops (the lid and the 9 loop), which are implicated in substrate recognition. PS-PLA1, mPA-PLA1 and mPA-PLA1 specifically hydrolyze PS and PA, respectively, and produce their corresponding lysophospholipids (lysophosphatidylserine and lysophosphatidic acid), which have been defined as lipid mediators with multiple biological functions. Thus, these PLA1s may have a physiological role in the production of these lysophospholipid mediators. The intracellular PLA1s consist of PA-preferring PLA1, KIAA0725p and p125 in mammals, all of which are conserved in a wide range of organisms and have been implicated in vesicular transport.

Phospholipid-mediated signaling in diseased myocardium

Phospholipase (PL)A1 is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids. Although PLA1 activities have been detected in many organisms and tissues, their functions have not been elucidated until recently. Currently, six extracellular and three intracellular PLA1 enzymes are known in mammals. The extracellular PLA1s consist of phosphatidylserine (PS)-specific PLA1 (PS-PLA1), membraneassociated phosphatidic acid (PA)-selective PLA1s (mPA-PLA1 and mPA-PLA1 ), hepatic lipase (HL), endothelial lipase (EL) and pancreatic lipas–elated protein (PLRP)-2, all of which belong to the lipase gene family. PS-PLA1, EL, mPA-PLA1 and mPA-PLA1 prefer phospholipid substrates, whereas HL and PLRP-2 show both PLA1 activity and lipase activity to hydrolyze triacylglycerol. EL has a role in high-density lipoprotein (HDL) metabolism by hydrolyzing phosphatidylcholine on HDL particles. PS-PLA1, mPA-PLA1 and mPA-PLA1 have distinct structural features in two surface loops (the lid and the 9 loop), which are implicated in substrate recognition. PS-PLA1, mPA-PLA1 and mPA-PLA1 specifically hydrolyze PS and PA, respectively, and produce their corresponding lysophospholipids (lysophosphatidylserine and lysophosphatidic acid), which have been defined as lipid mediators with multiple biological functions. Thus, these PLA1s may have a physiological role in the production of these lysophospholipid mediators. The intracellular PLA1s consist of PA-preferring PLA1, KIAA0725p and p125 in mammals, all of which are conserved in a wide range of organisms and have been implicated in vesicular transport.

Lipids and the endothelium: an update

In addition to being a major cause of morbidity, cardiovascular disease remains the dominant cause of all deaths in industrialized countries. Atherosclerosis is the principal underlying etiology for cardiovascular events and dyslipidemia, the main pathology leading to atherosclerosis. While lipid-lowering therapies, in particular the statins, have proven highly successful, monotherapy with low-density lipoprotein-cholesterol-lowering drugs appears to have reached its limit in terms of impeding cardiovascular events. Thus, other lipid-related risk factors, namely low levels of high-density lipoprotein (HDL)-cholesterol, are currently targeted. The most well-defined role of HDL is cholesterol efflux, the transportation of cholesterol from the periphery to the liver where it is subsequently removed. In addition, there are many other effects of HDL which are cardioprotective, including its antioxidative effects, its inhibition of lipid oxidation and, thus, foam cell formation, and its anti-inflammatory effect...

Quantitative analysis of SR-BI-dependent HDL retroendocytosis in hepatocytes and fibroblasts

Previous studies have suggested that HDL retroendocytosis may play a role in scavenger receptor class B type I (SR-BI)-dependent selective lipid uptake in a cell-specific manner. To investigate this possibility, we developed methods to quantitatively measure HDL uptake and resecretion in fibroblast (COS-7) and hepatocyte (HepG2) cells expressing exogenous SR-BI. Approximately 17% and 24% of HDL associated in an SR-BI-dependent manner with COS-7 and HepG2 cells, respectively, accumulates intracellularly after a 10 min incubation. To determine whether this intracellular HDL undergoes retroendocytosis, we developed a pulse-chase assay whereby internalized biotinylated (125)I-HDL(3) secreted from cells is quantitatively precipitated from cell supernatants using immobilized streptavidin. Our results show a rapid secretion of a portion of intracellular HDL from both cell types (representing 4-7% of the total cell-associated HDL) that is almost complete within 30 min (half-life approximately 10 min). In COS-7 cells, the calculated rate of HDL secretion ( approximately 0.5 ng HDL/mg/min) was >30-fold slower than the rate of SR-BI-dependent selective cholesteryl ester (CE) uptake ( approximately 17 ng HDL/mg/min), whereas the rate of release of HDL from the cell surface ( approximately 19 ng HDL/mg/min) was similar to the rate of selective CE uptake. Notably, the rate of SR-BI-dependent HDL resecretion in COS-7 and HepG2 cells was similar. BLT1, a compound that inhibits selective CE uptake, does not alter the amount of SR-BI-mediated HDL retroendocytosis in COS-7 cells. From these data, we conclude that HDL retroendocytosis in COS-7 and HepG2 cells is similar and that the vast majority of SR-BI-dependent selective uptake occurs at the cell surface in both cell types.

ApoA-I

See related article, pages 564–571 A link between homocysteine and atherothrombotic vascular disease was first suggested by McCully more than 30 years ago.1 The vascular lesions observed by McCully in children with inborn errors of homocysteine metabolism were fibrotic rather than lipid rich, suggesting the possibility that hyperhomocysteinemia may produce vascular pathology through a mechanism independent of altered lipid metabolism. Since that time, many epidemiological studies have confirmed that elevated plasma levels of total homocysteine (tHcy) are associated with an increased risk of coronary events, stroke, and venous thromboembolism.2–4 Most of the epidemiological data indicate that elevation of plasma tHcy is not associated with a significant change in plasma total cholesterol but is negatively associated with high density lipoprotein (HDL) cholesterol.5–7 An effect of homocysteine on HDL metabolism could be clinically important, because HDL protects from vascular disease not only by facilitating reverse cholesterol transport8 but also through its direct antiinflammatory properties.9 During the past decade, the development of animal models has led to rapid progress in defining the pathophysiological consequences of hyperhomocysteinemia in vivo. Experimental approaches to induce hyperhomocysteinemia in animals include the use of diets that are high in methionine and/or low in folate, as well as genetic approaches, such as the generation of knockout mice with targeted disruption of the cystathionine β-synthase ( Cbs ),10 methylene tetrahydrofolate reductase ( Mthfr ),11 or methionine synthase ( Mtr )12 genes. Like hyperhomocysteinemic humans, hyperhomocysteinemic animals develop endothelial dysfunction, hepatic lipid accumulation, and decreased plasma HDL cholesterol with minimal changes in plasma …