High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease.

High-density lipoproteins (HDL) are a heterogeneous class of molecules whose main function is to remove excess cholesterol through a mechanism called reverse transport, in which cholesterol is transported from peripheral organs and from arterial foam cells to the liver, where it is subsequently eliminated with bile. While its ability to eliminate excess cholesterol has always been viewed as its main feature, its beneficial effects go beyond this single effect. Many of the proteins that are associated with HDL are responsible for anti-oxidant and anti-inflammatory properties. These proteins that are associated with HDL during its generation and remodelling, are referred to as 'protein cargo', which has been extensively analysed by mass spectrometry analysis in healthy and diseased individuals. In this review, we discuss the pathway that leads to HDL formation and its subsequent remodelling and catabolism with regards to the possible involvement of HDL 'protein cargo' in Alzheimer's disease.

Ethanol-mediated upregulation of APOA1 gene expression in HepG2 cells is independent of de novo lipid biosynthesis.

BACKGROUND: Moderate alcohol intake in human increases HDL-cholesterol, and has protective effects against cardiovascular disease (CVD). Although de novo lipid synthesis inhibitors are highly effective in lowering total and LDL-cholesterol they have only modest effects on raising HDL-C. A better understanding of the mechanism of ethanol-mediated HDL-C regulation could suggest new therapeutic approaches for CVD. METHODS: Human hepatoblastoma (HepG2) and colorectal epithelial adenocarcinoma (Caco-2) cells were incubated in the presence of varying concentrations of ethanol in the culture medium, with or without addition of de novo lipid synthesis (DNLS) inhibitors (atorvastatin and/or TOFA). ApoA1 protein was measured by Western blot, and RNA of lipid pathway genes APOA1, APOC3, APOA4, APOB100, HMGCR, LDLR, and SREBF2 by quantitative RT-PCR. Lipoproteins (VLDL, LDL, and HDL) and lipids were also monitored. RESULTS: Ethanol stimulated ApoA1 protein (both cytoplasmic and secreted) and APOA1 RNA levels in HepG2 cells in a dose sensitive way, with ~ 50% upregulation at 100 mM ethanol in the medium. The effect was not observed in intestinal-derived Caco-2 cells. DNLS inhibitors did not block the upregulation of ApoA1 RNA by ethanol; TOFA alone produced a modest increase in ApoA1 RNA. Ethanol had no effect on ABCA1 protein levels. Addition of ethanol to the cell medium led to modest increases in de novo synthesis of total cholesterol, cholesteryl esters and triglycerides, and as expected these increases were blocked when the lipid synthesis inhibitors were added. Ethanol stimulated a small increase in HDL and VLDL but not LDL synthesis. Ethanol in the cell medium also induced modest but measurable increases in the RNA of APOC3, APOA4, APOB, LDLR, and HMGCR genes. Unlike APOA1, induction of RNA from APOC3 and APOA4 was also observed in Caco-2 cells as well as HepG2 cells. CONCLUSION: This study has verified the previously reported upregulation of APOA1 by exposure of HepG2, but not Caco-2 cells, to ethanol in the culture medium. It is shown for the first time that the effect is dependent on RNA polymerase II-mediated transcription, but not on de novo biosynthesis of cholesterol or fatty acids, and therefore is not a generalized metabolic response to ethanol exposure. Some other lipid pathway genes are also modulated by ethanol exposure of cells. The results reported here suggest that the proximal signaling molecule leading to increased APOA1 gene expression in response to ethanol exposure may be free acetate or acetyl-CoA. TAKE HOME: Upregulation of ApoA1 gene expression in hepatoma cells in culture, upon exposure to moderate ethanol concentrations in the medium, occurs at the level of RNA and is not dependent on new cholesterol or fatty acid synthesis. The primary signaling molecule may be free acetate or acetyl-CoA. These results are important for understanding the mechanism by which moderate alcohol consumption leads to upregulation of serum HDL-cholesterol in humans, and suggests new approaches to targeting HDL as a risk factor for cardiovascular disease.

Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis.

Fibroblast growth factor (FGF)19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analog, is currently in clinical development for treating nonalcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here, we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating LXR signaling while ameliorating hepatic steatosis. We further identify ABCA1 and FGF receptor 4 as mediators of this effect, and that administration of a HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF19-associated elevations in total cholesterol, HDL cholesterol (HDL-C), and LDL cholesterol in db/db mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF19 and NGM282 on cholesterol change. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for 7 days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF19 in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF19 analogs.

Chronic vitamin A-enriched diet feeding regulates hypercholesterolaemia through transcriptional regulation of reverse cholesterol transport pathway genes in obese rat model of WNIN/GR-Ob strain.

BACKGROUND & OBJECTIVES: Hepatic scavenger receptor class B1 (SR-B1), a high-density lipoprotein (HDL) receptor, is involved in the selective uptake of HDL-associated esterified cholesterol (EC), thereby regulates cholesterol homoeostasis and improves reverse cholesterol transport. Previously, we reported in euglycaemic obese rats (WNIN/Ob strain) that feeding of vitamin A-enriched diet normalized hypercholesterolaemia, possibly through hepatic SR-B1-mediated pathway. This study was aimed to test whether it would be possible to normalize hypercholesterolaemia in glucose-intolerant obese rat model (WNIN/GR/Ob) through similar mechanism by feeding identical vitamin A-enriched diet. METHODS: In this study, 30 wk old male lean and obese rats of WNIN/GR-Ob strain were divided into two groups and received either stock diet or vitamin A-enriched diet (2.6 mg or 129 mg vitamin A/kg diet) for 14 wk. Blood and other tissues were collected for various biochemical analyses. RESULTS: Chronic vitamin A-enriched diet feeding decreased hypercholesterolaemia and normalized abnormally elevated plasma HDL-cholesterol (HDL-C) levels in obese rats as compared to stock diet-fed obese groups. Further, decreased free cholesterol (FC) and increased esterified cholesterol (EC) contents of plasma cholesterol were observed, which were reflected in higher EC to FC ratio of vitamin A-enriched diet-fed obese rats. However, neither lecithin-cholesterol acyltransferase (LCAT) activity of plasma nor its expression (both gene and protein) in the liver were altered. On the contrary, hepatic cholesterol levels significantly increased in vitamin A-enriched diet fed obese rats. Hepatic SR-B1 expression (both mRNA and protein) remained unaltered among groups. Vitamin A-enriched diet fed obese rats showed a significant increase in hepatic low-density lipoprotein receptor mRNA levels, while the expression of genes involved in HDL synthesis, namely, ATP-binding cassette protein 1 (ABCA1) and apolipoprotein A-I, were downregulated. No such response was seen in vitamin A-supplemented lean rats as compared with their stock diet-fed lean counterparts. INTERPRETATION & CONCLUSIONS: Chronic vitamin A-enriched diet feeding decreased hypercholesterolaemia and normalized HDL-C levels, possibly by regulating pathways involved in HDL synthesis and degradation, independent of hepatic SR-B1 in this glucose-intolerant obese rat model.

Effects of n-3 polyunsaturated fatty acids high fat diet intervention on the synthesis of hepatic high-density lipoprotein cholesterol in obesity-insulin resistance rats.

BACKGROUND: n-3 polyunsaturated fatty acids (PUFA) have previously been demonstrated in association with a reduced risk of chronic diseases, including insulin resistance, cancer and cardiovascular disease. In the present study, we analyzed the effects of n-3 PUFA-rich perilla oil (PO) and fish oil (FO) high fat diet intervention against the synthesis of hepatic high-density lipoprotein cholesterol (HDL-c) in obesity-insulin resistance model rats. METHODS: In the modeling period, the male SD rats were randomly divided into 2 groups. The rats in the high fat (HF) group were given a high fat pure diet containing 20.62% lard. In the intervention period, the model rats were intervened with purified high-fat diets rich in PO or FO, containing same energy content with high fat pure diet in HF. After the intervention, the protein and mRNA expressions status of the key genes involved in synthesis of hepatic HDL-c were measured for further analytic comparison. RESULTS: The obesity-insulin resistance model rats were characterized by surprisingly high levels of serum triglyceride (TG) and increased body weight (P < 0.05, each). After the intervention, there were no apparent changes in the serum HDL-c and total cholesterol (TCH). In addition, the FO could up-regulate the hepatic adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1) mRNA (P < 0.01) and protein expressions, as well as increase the level of serum apolipoprotein A-1 (apoA-1) (P < 0.0001), and elevate the hepatic apoA-1mRNA expression (P < 0.01). Different from FO, the PO specifically elevated the hepatic ABCA1mRNA expression (P < 0.01). CONCLUSIONS: The FO high fat diets promoted the synthesis of HDL-c in the obesity-insulin resistance rats.

ABCA1-dependent sterol release: sterol molecule specificity and potential membrane domain for HDL biogenesis.

Mammalian cells synthesize various sterol molecules, including the C30 sterol, lanosterol, as cholesterol precursors in the endoplasmic reticulum. The build-up of precursor sterols, including lanosterol, displays cellular toxicity. Precursor sterols are found in plasma HDL. How these structurally different sterols are released from cells is poorly understood. Here, we show that newly synthesized precursor sterols arriving at the plasma membrane (PM) are removed by extracellular apoA-I in a manner dependent on ABCA1, a key macromolecule for HDL biogenesis. Analysis of sterol molecules by GC-MS and tracing the fate of radiolabeled acetate-derived sterols in normal and mutant Niemann-Pick type C cells reveal that ABCA1 prefers newly synthesized sterols, especially lanosterol, as the substrates before they are internalized from the PM. We also show that ABCA1 resides in a cholesterol-rich membrane domain resistant to the mild detergent, Brij 98. Blocking ACAT activity increases the cholesterol contents of this domain. Newly synthesized C29/C30 sterols are transiently enriched within this domain, but rapidly disappear from this domain with a half-life of less than 1 h. Our work shows that substantial amounts of precursor sterols are transported to a certain PM domain and are removed by the ABCA1-dependent pathway.

Hepatic cholesterol homeostasis: is the low-density lipoprotein pathway a regulatory or a shunt pathway?

OBJECTIVE: The hypothesis that cholesterol that enters the cell within low-density lipoprotein (LDL) particles rapidly equilibrates with the regulatory pool of intracellular cholesterol and maintains cholesterol homeostasis by reducing cholesterol and LDL receptor synthesis was validated in the fibroblast but not in the hepatocyte. Accordingly, the present studies were designed to compare the effects of cholesterol that enters the hepatocyte within an LDL particle with those of cholesterol that enters via other lipoprotein particles. APPROACH AND RESULTS: We measured cholesterol synthesis and esterification in hamster hepatocytes treated with LDL and other lipoprotein particles, including chylomicron remnants and VLDL. Endogenous cholesterol synthesis was not significantly reduced by uptake of LDL, but cholesterol esterification (280%) and acyl CoA:cholesterol acyltransferase 2 expression (870%) were increased. In contrast, cholesterol synthesis was significantly reduced (70% decrease) with other lipoprotein particles. Furthermore, more cholesterol that entered the hepatocyte within LDL particles was secreted within VLDL particles (480%) compared with cholesterol from other sources. CONCLUSIONS: Much of the cholesterol that enters the hepatocyte within LDL particles is shunted through the cell and resecreted within VLDL particles without reaching equilibrium with the regulatory pool.

A big role for small RNAs in HDL homeostasis.

High-density lipoproteins play a central role in systemic cholesterol homeostasis by stimulating the efflux of excess cellular cholesterol and transporting it to the liver for biliary excretion. HDL has long been touted as the "good cholesterol" because of the strong inverse correlation of plasma HDL cholesterol levels with coronary heart disease. However, the disappointing outcomes of recent clinical trials involving therapeutic elevations of HDL cholesterol have called this moniker into question and revealed our lack of understanding of this complex lipoprotein. At the same time, the discovery of microRNAs (miRNAs) that regulate HDL biogenesis and function have led to a surge in our understanding of the posttranscriptional mechanisms regulating plasma levels of HDL. Furthermore, HDL has recently been shown to selectively transport miRNAs and thereby facilitate cellular communication by shuttling these potent gene regulators to distal tissues. Finally, that miRNA cargo carried by HDL may be altered during disease states further broadened our perspective of how this lipoprotein can have complex effects on target cells and tissues. The unraveling of how these tiny RNAs govern HDL metabolism and contribute to its actions promises to reveal new therapeutic strategies to optimize cardiovascular health.

From evolution to revolution: miRNAs as pharmacological targets for modulating cholesterol efflux and reverse cholesterol transport.

There has been strong evolutionary pressure to ensure that an animal cell maintains levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies.

Naturally occurring variant of mouse apolipoprotein A-I alters the lipid and HDL association properties of the protein.

Plasma HDL levels are inversely associated with atherosclerosis. Inbred mouse strains differ in plasma HDL levels and susceptibility to atherosclerosis. Atherosclerosis-susceptible C57BL/6J mice possess plasma HDL levels 2-fold lower than atherosclerosis-resistant FVB/NJ mice. Polymorphisms have been previously identified between the two mouse strains in the major HDL apolipoproteins, ApoA-I and ApoA-II, which may affect their function on HDL. To begin to understand the HDL differences, we here report on a detailed comparison of the lipid-associated functions of the two mouse ApoA-I proteins. We demonstrate that these polymorphisms significantly alter the protein self-association properties, the ability of the proteins to clear lipid micelles from solution, and their binding affinity for mature mouse HDL. The changes in lipid binding do not appear to alter the ability of the protein to promote cholesterol efflux from cells or the formation of nascent HDL from primary hepatocytes. These apolipoprotein polymorphisms do not change the rate at which HDL protein or cholesterol are catabolized in vivo. Although the presence of the polymorphisms in ApoA-I alters important factors in HDL formation, the basis for the differences in the HDL plasma levels observed in the various mouse strains is more complex and requires additional investigation.

Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells.

The lipidation of apoA-I in liver greatly influences HDL biogenesis and plasma HDL levels by stabilizing the secreted apoA-I. Niacin is the most effective lipid-regulating agent clinically available to raise HDL. This study was undertaken to identify regulatory mechanisms of niacin action in hepatic lipidation of apoA-I, a critical event involved in HDL biogenesis. In cultured human hepatocytes (HepG2), niacin increased: association of apoA-I with phospholipids and cholesterol by 46% and 23% respectively, formation of lipid-poor single apoA-I molecule-containing particles up to ~2.4-fold, and pre ß 1 and α migrating HDL particles. Niacin dose-dependently stimulated the cell efflux of phospholipid and cholesterol and increased transcription of ABCA1 gene and ABCA1 protein. Mutated DR4, a binding site for nuclear factor liver X receptor alpha (LXR α ) in the ABCA1 promoter, abolished niacin stimulatory effect. Further, knocking down LXR α or ABCA1 by RNA interference eliminated niacin-stimulated apoA-I lipidation. Niacin treatment did not change apoA-I gene expression. The present data indicate that niacin increases apoA-I lipidation by enhancing lipid efflux through a DR4-dependent transcription of ABCA1 gene in HepG2 cells. A stimulatory role of niacin in early hepatic formation of HDL particles suggests a new mechanism that contributes to niacin action to increase the stability of newly synthesized circulating HDL.

Hydroxychloroquine use associated with improvement in lipid profiles in rheumatoid arthritis patients.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Disease-modifying therapies that improve risk factors for CVD, such as dyslipidemia, are desired. This study used an electronic health record to determine if hydroxychloroquine (HCQ) use was associated with an improvement in lipid levels in an inception RA cohort. METHODS: All adult individuals with the initial diagnosis of RA between January 1, 2001, and March 31, 2008, were identified (n=1,539). Only patients with at least one lipid level post-RA diagnosis were included (n=706). Information on demographics, medical history, body mass index (BMI), laboratory measures, and medications were collected at office visits. Potential risk and protective factors for dyslipidemia were controlled for in linear mixed-effects regression models for low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, triglycerides, LDL/HDL, and total cholesterol/HDL. RESULTS: Patients were 69% women and 98% white, with a median age of 65 years and a median BMI of 29.8 kg/m2. In the adjusted regression models, HCQ use was associated with the following average differences in lipids: LDL decrease of 7.55 mg/dl (P<0.001), HDL increase of 1.02 mg/dl (P=0.20), total cholesterol decrease of 7.70 mg/dl (P=0.002), triglycerides decrease of 10.91 mg/dl (P=0.06), LDL/HDL decrease of 0.136 (P=0.008), and total cholesterol/HDL decrease of 0.191 (P=0.006), which were stable over time. CONCLUSION: Use of HCQ in this RA cohort was independently associated with a significant decrease in LDL, total cholesterol, LDL/HDL, and total cholesterol/HDL. Considering these results, its safety profile, and low cost, HCQ remains a valuable initial or adjunct therapy in this patient population at high risk for CVD.

HDL-C concentration is related to markers of absorption and of cholesterol synthesis: Study in subjects with low vs. high HDL-C.

BACKGROUND: The antiatherogenic functions of high density lipoprotein (HDL-C) include its role in reverse cholesterol transport, but to what extent the concentration of HDL-C interferes with the whole-body cholesterol metabolism is unknown. Therefore, we measured markers of body cholesterol synthesis (desmosterol and lathosterol) and of intestinal cholesterol absorption (campesterol and ß-sitosterol) in healthy subjects that differ according to their plasma HDL-C concentrations. METHODS: Healthy participants presented either low HDL-C (< 40 mg/dl, n=33, 17 male and 16 female) or high HDL-C (> 60 mg/dl, n=33, 17 male and 16 female), BMI< 30 kg/m², were paired according to age and gender, without secondary factors that might interfere with their plasma lipid concentrations. Plasma concentrations of non-cholesterol sterols were measured by the combined GC-MS analysis. RESULTS: Plasma desmosterol did not differ between the two groups; however, as compared with the high HDL-C participants, the low HDL-C participants presented higher concentration of lathosterol and lower concentration of the intestinal cholesterol absorption markers campesterol and ß-sitosterol. CONCLUSION: Plasma concentrations of HDL, and not the activities of LCAT and CETP that regulate the reverse cholesterol transport system, correlate with plasma sterol markers of intestinal cholesterol absorption directly, and of cholesterol synthesis reciprocally.

A possible mechanism linking hyperglycemia and reduced high-density lipoprotein cholesterol levels in diabetes.

This study investigated the role of glucose in the biogenesis of high-density lipoprotein cholesterol (HDL-C). Mouse primary peritoneal macrophages were harvested and maintained in Dulbecco's modified Eagle's medium (DMEM) containing glucose of various concentrations. The cells were divided into 3 groups in terms of different glucose concentrations in the cultures: Control group (5.6 mmol/L glucose), high glucose concentration groups (16.7 mmol/L and 30 mmol/L glucose). ATP-binding cassette transporter A1 (ABCA1) mRNA expression in the macrophages was detected by semi-quantitative RT-PCR 24, 48 and 72 h after glucose treatment. The results showed that ABCA1 mRNA expression in the 16.7 mmol/L glucose group was not significantly different from that in the control group at all testing time points (P>0.05 for each). In the 30 mmol/L glucose group, macrophage ABCA1 mRNA expression was not changed significantly at 24 h (P=0.14), but was substantially decreased by 40.4% at 48 h (P=0.009) and by 48.1% at 72 h (P=0.015) as compared with that in the control group. It was concluded that ABCA1 is of vital importance for HDL-C biogenesis. High glucose may hamper HDL-C biogenesis by decreasing ABCA1 expression, which contributes to low HDL-C level in diabetes.

Association of R230C ABCA1 gene variant with low HDL-C levels and abnormal HDL subclass distribution in Mexican school-aged children.

BACKGROUND: The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults. METHODS: We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. HDL subclass distribution was analyzed in a subgroup of 81 age, gender and BMI-matched children. RESULTS: Individuals carrying the C230 allele showed a significantly lower HDL-C levels (P=2.9x10(-8)), and higher TC/HDL-C ratio, BMI, BMI z-score and percent fat mass (P=0.001, 0.049, 0.032 and 0.039, respectively). HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (P<0.05). Moreover, the proportion of HDL(2b) was lower, while the proportion of HDL(3a) and HDL(3b) particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (P<0.05). CONCLUSIONS: Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children.

Genetic causes of high and low serum HDL-cholesterol.

Plasma levels of HDL cholesterol (HDL-C) have a strong inherited basis with heritability estimates of 40-60%. The well-established inverse relationship between plasma HDL-C levels and the risk of coronary artery disease (CAD) has led to an extensive search for genetic factors influencing HDL-C concentrations. Over the past 30 years, candidate gene, genome-wide linkage, and most recently genome-wide association (GWA) studies have identified several genetic variations for plasma HDL-C levels. However, the functional role of several of these variants remains unknown, and they do not always correlate with CAD. In this review, we will first summarize what is known about HDL metabolism, monogenic disorders associated with both low and high HDL-C levels, and candidate gene studies. Then we will focus this review on recent genetic findings from the GWA studies and future strategies to elucidate the remaining substantial proportion of HDL-C heritability. Comprehensive investigation of the genetic factors conferring to low and high HDL-C levels using integrative approaches is important to unravel novel pathways and their relations to CAD, so that more effective means of diagnosis, treatment, and prevention will be identified.

Aroused versus calm positive affects as predictors of lipids.

OBJECTIVE: The authors hypothesized that high-pleasure low-arousal (HPLA) would predict a subsequent decrease of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TRI), as well as a subsequent increase of high-density lipoprotein cholesterol (HDL-C). The authors also hypothesized that high-pleasure high-arousal (HPHA) would have the opposite effects on these blood lipids, predicting a subsequent increase of LDL-C and TRI, and a decrease of HDL-C. DESIGN: Participants were 990 male and 595 female apparently healthy employees who underwent a routine periodic health examination at two points in time, Time 1 (T1) and Time 2 (T2), about 24 months apart. Data were analyzed separately for the men and women, and the authors controlled for possible confounders shown in past research to be implicated with hyperlipidemia. MAIN OUTCOME MEASURES: HPHA and HPLA were assessed based on the Job-Related Affective Well-Being Scale, while LDL-C, TRI, and HDL-C were assessed based on fasting blood samples. RESULTS: For the men, support for our hypotheses was found relative to HDL-C and TRI. The authors did not find support for our hypotheses for thee women. CONCLUSION: Our findings suggest that for men, the two types of positive affects may have opposite physiological consequences with respect to subsequent changes in blood lipid levels.