Plasma High-density Lipoprotein Cholesterol Concentrations Research Articles

No effect of liraglutide on high density lipoprotein apolipoprotein AI kinetics in patients with type 2 diabetes

AimThe catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D. MethodsAn in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of liraglutide, using a bolus of l-[1–13C]leucine followed by a 16-hour constant infusion. ResultsLiraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m2, P = 0.012), HbA1c (7.1 ± 1.1 vs 9.6 ± 2.6%, P = 0.003), HOMA-IR (5.5 ± 1.9 vs 11.6 ± 11.2, P = 0.003), fasting triglycerides (1.76 ± 0.37 vs 2.48 ± 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 ± 0.81 vs 2.66 ± 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 ± 0.26 vs 0.97 ± 0.19 mmol/l, P = 1; 3169 ± 1561 vs 2618 ± 1651 µg/l, P = 0.160), similar to triglyceride content in HDL (5.13 ± 1.73 vs 5.39 ± 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 ± 0.11 vs 0.38 ± 0.11 pool/day, P = 0.375), nor its production rate (0.44 ± 0.13 vs 0.49 ± 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 ± 0.19 vs 1.29 ± 0.14 g/l, P = 0.386). ConclusionSix months of treatment with 1.2 mg/day of liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied.

Differential Effects of Two Isocaloric Healthy Diets on Postprandial Lipid Responses in Individuals with Type 2 Diabetes.

High blood concentrations of triglycerides (TG) in the postprandial period have been shown to be more closely associated with the risk of cardiovascular disease (CVD) than fasting values in individuals with type 2 diabetes (T2D). Dietary changes are the primary determinants of postprandial lipid responses. We investigated the effects of an isocaloric multifactorial diet, rich in n-3 PUFA, MUFA, fiber, polyphenols, and vitamins, compared to an isocaloric diet, containing the same amount of MUFA, on the postprandial lipid response in T2D individuals. Following a randomized, controlled, parallel group design, 43 (25 male/18 female) T2D individuals were assigned to an isocaloric multifactorial (n = 21) or a MUFA-rich diet (n = 22). At the beginning and after the 8 weeks of dietary intervention, the concentrations of plasma triglycerides, total cholesterol, HDL cholesterol, and non-HDL cholesterol were detected at fasting and over a 4-h test meal with the same composition as the prescribed diet. The concentrations of fasting plasma triglycerides, total cholesterol, HDL cholesterol, and non-HDL cholesterol did not change after both diets. Compared with the MUFA diet, the 8-week multifactorial diet significantly lowered the postprandial response, which was evaluated as the incremental area under the curve (iAUC), of triglycerides by 33% (64 ± 68 vs. 96 ± 50 mmol/L·240 min, mean ± SD, respectively, p = 0.018), total cholesterol by 105% (-51 ± 33 vs. -25 ± 29, p = 0.013), and non-HDL cholesterol by 206% (-39 ± 33 vs. -13 ± 23, p = 0.013). In T2D individuals, a multifactorial diet, characterized by several beneficial components, improved the postprandial lipid response compared to a MUFA diet, generally considered a healthy diet being reduced in saturated fat, and probably contributed to the reduction of cardiovascular risk.

CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice.

CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.

ABO gene polymorphisms are associated with acute coronary syndrome and with plasma concentration of HDL-cholesterol and triglycerides.

The role of ABO gene polymorphisms in acute coronary syndrome (ACS) and lipid metabolism is increasingly recognized. We investigated whetherABO gene polymorphisms are significantly associated with ACS and the plasma lipid profile. SixABOgene polymorphisms (rs651007T/C, rs579459T/C, rs495928T/C, rs8176746T/G, rs8176740A/T, and rs512770T/C) were determined by 5'exonuclease TaqMan assays in 611 patients with ACS and 676 healthy controls. The results demonstrated that the rs8176746Tallele was associated with a lower risk of ACS under the co-dominant, dominant, recessive, over-dominant, and additive models (P= 0.0004,P= 0.0002,P= 0.039, P= 0.0009, andP= 0.0001, respectively). Furthermore, under co-dominant, dominant, and additive models, the rs8176740Aallele was associated with a lower risk of ACS(P= 0.041,P= 0.022, andP= 0.039, respectively). On the other hand, the rs579459Callele was associated with a lower risk of ACS under the dominant, over-dominant, and additive models (P= 0.025,P= 0.035, andP= 0.037, respectively). In a subanalysis performed with the control group, rs8176746Tand rs8176740Aalleles were associated with low systolic blood pressure and with both high high-density lipoprotein-cholesterol (HDL-C) and low triglyceride plasma concentrations, respectively. In conclusion, ABOgene polymorphisms were associated with a lower risk of ACS, and lower systolic blood pressure and plasma lipid levels, suggesting a causal relationship between ABO blood groups and the incidence of ACS.

Effects of the Ketogenic Diet on Metabolic Syndrome

The global prevalence of obesity and metabolic syndrome and its pathophysiologic sequela are currently approaching epidemic proportions, with unacceptable levels in much of Westernized and economically developed society. The clinical stigmata of metabolic syndrome typically include the comorbidities of obesity, hypertension, non-insulin dependent diabetes, and hyperlipidemia with decreased plasma high density lipoprotein concentrations. In addition, a common finding of hyperinsulinemia and insulin resistance typical of high carbohydrate diets often accompanies the syndrome. The incorporation of the insulin sparing ketogenic diet as a dietary strategy for the treatment of metabolic syndrome may bring about improvements in insulin action and substrate utilization in peripheral tissues with at least a partial if not significant resolution of the syndrome. Thus, the ketogenic diet in addition to adaptations toward a healthy lifestyle and pharmacologic therapies have been explored as potential mechanisms to resolve the pathophysiologic sequela of obesity and metabolic syndrome and their impact on the delivery of healthcare. Metabolic syndrome (MetS) is a condition defined as a clustering of risk factors that is strongly associated with obesity, heart disease, and diabetes [22]. It has recently been estimated that the global prevalence of MetS has reached epidemic levels including the U.S.A., where it has been estimated that 20% to 25% of the adult global population meets the diagnostic criterion for MetS [3], which may be established when at least three of the five primary risk factors are present. The risk factors include a large waistline (abdominal or visceral obesity), high plasma triglyceride levels, low plasma HDL cholesterol concentrations, elevated blood pressure, and fasting hyperglycemia. The standard and most effective treatments for MetS to date have been incorporation of lifestyle changes, with dietary interventions being one of the major effective lifestyle modifications utilized to treat both obesity and MetS [14];[41]. The Ketogenic Diet (KD) is one dietary intervention that may have the potential to improve MetS risk factors. Historically, one of the primary uses of the KD has been to treat epilepsy, however, there is substantial evidence that it may also help to improve other conditions and illnesses, including obesity and MetS [30]; [48]; [35]. Despite this potential, certain dietary misconceptions may have prevented or slowed further research on the KD applications to weight control and use of the KD, particularly the emergence of the national dietary guidelines that have now promoted a low-fat, high-carbohydrate diet for several decades [18]; [51]; [52]. The purpose of this paper is to conduct a review of the literature regarding MetS, the KD, and the implications of the KD as a treatment for obesity and MetS. Existing research is systematically reviewed regarding the KD’s potential to address MetS and MetS risk factors. The results of the review indicate the validity of the diet and the need for further research on the KD and its potential to address the benefits, potential risks and clinical efficacy of the KD on reducing the pathophysiologic sequalae of obesity and MetS. MetS = Metabolic Syndrome, KD = ketogenic diet, KB = ketone bodies, including metabolic remnants acetoacetate (AcAc),3-beta-hydroxybutyrate (3HB), and acetone, PSMF = Protein Sparing Modified Fast, HDL, HDL-C= plasma high density cholesterol lipoprotein, LDL, LDL-C = low density cholesterol lipoprotein, TG, TRIG = plasma triglycerides, CRP = C-reactive protein, GLUT4 = Glucose Transporter 4, and insulin-linked cellular entity, ATP = Adenosine tri-phosphate, a high energy phosphate, CCK = cholecystokinin, CR = calorie restricted diet, LFD = low fat diet, LCKD = low calorie ketogenic diet, BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure, A(1c) = glycosylated hemoglobin fraction, NHLBI = National Heart, Lung and Blood Institute of the National Institutes of Health

Epigenome-wide association study of plasma lipids in West Africans: the RODAM study.

DNA-methylation has been associated with plasma lipid concentration in populations of diverse ethnic backgrounds, but epigenome-wide association studies (EWAS) in West-Africans are lacking. The aim of this study was to identify DNA-methylation loci associated with plasma lipids in Ghanaians. We conducted an EWAS using Illumina 450k DNA-methylation array profiles of extracted DNA from 663 Ghanaian participants. Differentially methylated positions (DMPs) were examined for association with plasma total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, and triglycerides concentrations using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, and technical covariates. Findings were replicated in independent cohorts of different ethnicities. We identified one significantly associated DMP with triglycerides (cg19693031 annotated to TXNIP, regression coefficient beta-0.26, false discovery rate adjusted p-value 0.001), which replicated in-silico in South African Batswana, African American, and European populations. From the top five DMPs with the lowest nominal p-values, two additional DMPs for triglycerides (CPT1A, ABCG1), two DMPs for LDL-cholesterol (EPSTI1, cg13781819), and one for TC (TXNIP) replicated. With the exception of EPSTI1, these loci are involved in lipid transport/metabolism or are known GWAS-associated loci. The top 5 DMPs per lipid trait explained 9.5% in the variance of TC, 8.3% in LDL-cholesterol, 6.1% in HDL-cholesterol, and 11.0% in triglycerides. The top DMPs identified in this study are in loci that play a role in lipid metabolism across populations, including West-Africans. Future studies including larger sample size, longitudinal study design and translational research is needed to increase our understanding on the epigenetic regulation of lipid metabolism among West-African populations. European Commission under the Framework Programme (grant number: 278901).

Plasma Total and Lipoprotein Cholesterol, Liver Cholesterol and Fecal Cholesterol Excretion in Hamsters Fed Fiber Diets

The effect of dietary fibers on plasma lipids, liver cholesterol and fecal cholesterol excretion was investigated in hamsters. Male 9- to 11-wk-old Golden-Syrian hamsters (n = 155) were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 5 wk to elevate plasma lipid concentrations. Sixteen animals with elevated plasma total cholesterol were randomly assigned to each treatment group: control, oat bran, guar gum, cellulose, xylan and terminal groups. After 4 wk of fiber diet consumption, the plasma total cholesterol concentrations were significantly decreased in the oat bran, guar gum and xylan groups (16, 12 and 15%, respectively) (P < 0.05). Plasma HDL cholesterol concentration was significantly decreased only in the guar gum group (12%) (P < 0.05). The combined plasma VLDL+LDL cholesterol concentrations were significantly lowered by the oat bran, xylan and cellulose diets (38, 34 and 40%, respectively) (P < 0.05). After 4 wk of control diet consumption, the liver cholesterol concentration quadrupled to 10.6 mumol cholesterol/g liver (P < 0.05). After 4 wk of consumption of the treatment diets, liver cholesterol was further increased (P < 0.05) only in the cellulose group, to 14.5 mumol cholesterol/g liver. The total fecal cholesterol excretion was the highest (P < 0.05) in the oat bran group. In the present study, oat bran, guar gum and xylan were effective hypocholesterolemic agents in hamsters.

Circadian rhythm parameters and physical activity associated with cardiometabolic risk factors in the PREVIEW lifestyle study

The aim of this study was an assessment of post hoc associations among circadian rhythm parameters, physical activity (PA), and cardiometabolic risk factors in adults with obesity and prediabetes after 3 years of weight loss maintenance. Circadian rhythm parameters (continuous wrist-temperature measurements), PA, systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, remnant cholesterol, triacylglycerol, and C-reactive protein (CRP) concentrations were determined in 91 free-living participants (mean [SD], age=56.6 [10] years; BMI =28.2 [4.0]; homeostatic model assessment of insulin resistance [HOMA-IR]=3.2 [3.1]) and in 38 participants in sedentary respiration chamber conditions (age=56.6[10] years; BMI=28.5[4.0]; HOMA-IR=3.3 [1.4]). Associations of circadian rhythm parameters and PA with cardiometabolic risk factors were determined using factor analyses followed by Pearson correlations. Values of cardiometabolic risk factors were similar, whereas circadian rhythm parameters and PA differed significantly (p < 0.05) between conditions. In both conditions, parameters indicating a robust circadian rhythm associated inversely with CRP and positively with plasma HDL-C concentrations. In free-living conditions, PA associated inversely with SBP and HR and positively with HDL-C and robust circadian rhythm parameters. In sedentary conditions, PA associated positively with HR and inversely with robust circadian rhythm parameters. PA mediated the inverse association of parameters indicating a robust circadian rhythm with SBP in free-living conditions. In adults with obesity and prediabetes, parameters indicating a robust circadian rhythm were, independently of PA, associated with lower cardiometabolic risk and CRP. Only in free-living conditions, PA mediated the association of higher circadian stability with lower SBP.

Serum opacity factor rescues fertility among female Scarb1−/− mice by reducing HDL-free cholesterol bioavailability

Human female infertility, 20% of which is idiopathic, is a public health problem for which better diagnostics and therapeutics are needed. A novel cause of infertility emerged from studies of female mice deficient in the HDL receptor gene (Scarb1). These mice are infertile and have high plasma HDL cholesterol (C) concentrations, due to elevated HDL-free cholesterol (FC), which transfers from HDL to all tissues. Previous studies have indicated that oral delivery of probucol, an HDL-lowering drug, to female Scarb1−/− mice reduces plasma HDL-C concentrations and rescues fertility. Additionally, serum opacity factor (SOF), a bacterial virulence factor, disrupts HDL structure, and bolus SOF injection into mice reduces plasma HDL-C concentrations. Here, we discovered that delivering SOF to female Scarb1−/− mice with an adeno-associated virus (AAVSOF) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAVSOF did not alter ovary-FC content, the ovary-mol% FC correlated with plasma HDL-mol% FC in a fertility-dependent way. Therefore, reversing the abnormal plasma microenvironment of high plasma HDL-mol% FC in female Scarb1-/- mice rescues fertility. These data provide the rationale to search for similar mechanistic links between HDL-mol% FC and infertility and the rescue of fertility in women by reducing plasma HDL-mol% FC.

Sugar-Sweetened Beverage Consumption and Plasma Lipoprotein Cholesterol, Apolipoprotein, and Lipoprotein Particle Size Concentrations in US Adults

Prospective cohort studies have found a relation between sugar-sweetened beverage (SSB) consumption (sodas and fruit drinks) and dyslipidemia. There is limited evidence linking SSB consumption to emerging features of dyslipidemia, which can be characterized by variation in lipoprotein particle size, remnant-like particle (RLP), and apolipoprotein concentrations. To examine the association between SSB consumption and plasma lipoprotein cholesterol, apolipoprotein, and lipoprotein particle size concentrations among US adults. We examined participants from the Framingham Offspring Study (FOS; 1987-1995, n = 3047) and the Women's Health Study (1992, n = 26,218). Concentrations of plasma LDL cholesterol, apolipoprotein B (apoB), HDL cholesterol, apolipoprotein A1 (apoA1), triglyceride (TG), and non-HDL cholesterol, as well as total cholesterol:HDL cholesterol ratio and apoB:apoA1 ratio, were quantified in both cohorts; concentrations of apolipoprotein E, apolipoprotein C3, RLP-TG, and RLP cholesterol (RLP-C) were measured in the FOS only. Lipoprotein particle sizes were calculated from nuclear magnetic resonance signals for lipoprotein particle subclass concentrations (TG-rich lipoprotein particles [TRL-Ps]: very large, large, medium, small, and very small; LDL particles [LDL-Ps]: large, medium, and small; HDL particles [HDL-Ps]: large, medium, and small). SSB consumption was estimated from food frequency questionnaire data. We examined the associations between SSB consumption and all lipoprotein and apoprotein measures in linear regression models, adjusting for confounding factors such as lifestyle, diet, and traditional lipoprotein risk factors. SSB consumption was positively associated with LDL cholesterol, apoB, TG, RLP-TG, RLP-C, and non-HDL cholesterol concentrations and total cholesterol:HDL cholesterol and apoB:apoA1 ratios; and negatively associated with HDL cholesterol and apoA1 concentrations (P-trend range: <0.0001 to 0.008). After adjustment for traditional lipoprotein risk factors, SSB consumers had smaller LDL-P and HDL-P sizes; lower concentrations of large LDL-Ps and medium HDL-Ps; and higher concentrations of small LDL-Ps, small HDL-Ps, and large TRL-Ps (P-trend range: <0.0001 to 0.001). Higher SSB consumption was associated with multiple emerging features of dyslipidemia that have been linked to higher cardiometabolic risk in US adults.

Modulatory effect of berberine on plasma lipoprotein (or lipid) profile: a review.

Berberine is a bioactive isoquinoline alkaloid compound extracted from various medicinal plants, such as Barberry. Berberine shows various pharmacological properties that are mainly attributed to its anti-inflammatory and antioxidant effects. A growing body of evidence has shown that berberine influences cholesterol metabolism, and consequently, may ameliorate dyslipidemias and atherosclerosis. Plasma high-density lipoprotein cholesterol (HDL-C) is known to have an independent negative association with incident cardiovascular disease (CVD). However, several outcomes trials and genetic studies have failed to meet expecting the beneficial effects of elevating plasma HDL-C concentrations. Hence, investigations are currently focused on enhancing the functionality of HDL particles, independent of their plasma concentrations. HDL particles show various qualities because of a heterogeneous composition. Consistent with complex metabolism and composition, various biological functions are found for HDL, such as anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic activities. Protective effects of berberine may impact the functionality of HDL; therefore, the present literature review was intended to determine whether berberine can amplify HDL function. It was concluded that berberine may regulate markers of HDL activity, such as apo-AI, cholesterol efflux, LCAT, PON1, and S1P activities and levels. Consequently, berberine may recuperate conditions with dysfunctional HDL and, therefore, have the potential to emerge as a therapeutic agent. However, further human trials of berberine are warranted to evaluate its impact on HDL function and cholesterol metabolism.

Orally administered zingerone does not mitigate alcohol-induced hepatic oxidative stress in growing Sprague Dawley rat pups

Neonatal alcohol exposure (NAE) can induce oxidative stress. We determined whether zingerone (ZO), a phytochemical with anti-oxidant activity, can mitigate the negative impact of neonatal alcohol-induced oxidative stress. Seventy ten-day-old Sprague-Dawley rat pups (35 male, 35 female) were randomly assigned and administered the following treatment regimens daily from postnatal day (PND) 12–21: group 1 – nutritive milk (NM), group 2 – NM +1 g/kg ethanol (Eth), group 3 – NM + 40 mg/kg ZO, group 4 – NM + Eth + ZO. Growth performance, blood glucose and plasma triglycerides (TGs), total cholesterol, HDL-cholesterol, leptin and insulin concentration were determined. Cytochrome p450E21(CYP2E1) and thiobarbituric acid (TBARS); markers of hepatic oxidative stress and catalase, superoxide dismutase (SOD) and total glutathione (GSH), anti-oxidant markers of the pups were determined. Oral administration of ethanol (NM + Eth), zingerone (NM + ZO) and combined ethanol and zingerone (NM + Eth + ZO) did not affect the growth performance and insulin and leptin concentration of the rats (p > 0.05). Ethanol significantly reduced plasma TGs concentration of female rats (p = 0.04 vs control). However, ethanol and/or its combination with zingerone decreased hepatic GSH (p = 0.02 vs control) and increased CYP2E1 (p = 0.0002 vs control) activity in male rat pups. Zingerone had no effect (p > 0.05 vs control) on the rats' CYP2E1, GSH, SOD and catalase activities. Neonatal alcohol administration elicited hepatic oxidative stress in male rat pups only, showing sexual dimorphism. Zingerone (NM + ZO) prevented an increase in CYP2E1 activity and a decrease in GSH concentration but did not prevent the alcohol-induced hepatic oxidative stress in the male rat pups.

Abstract 499: Serum Opacity Factor Therapy Alters Plasma, Erythrocyte And Tissue Cholesterol Content In The Dysfunctional High Density Lipoprotein Scarb1 -/- Mouse Model

Aim: In humans, very high plasma HDL-cholesterol concentrations are associated with increased all cause- and atherosclerotic cardiovascular disease (ASCVD)-mortality. The HDL receptor-deficient mouse (Scarb1 -/- ) is a robust model of this phenotype having high free cholesterol (FC) bioavailability due to too many FC-rich HDL particles. Clinically, plasma LDL and HDL are quantified according to total cholesterol = FC + cholesteryl esters (CE), which likely contribute to ASCVD pathophysiology differently. Despite higher HDL, Scarb1 -/- mice have more ASCVD on a Western diet, and increased mol% FC in ovaries, erythrocytes, heart, lung, female liver and macrophages, tissues that are associated with female infertility, impaired cell maturation, cardiac dysfunction and atherosclerosis. Bacterial serum opacity factor (SOF) reduces plasma cholesterol ~ 40% by diverting HDL-cholesterol to the hepatic LDLR. Hypothesis: Adeno-associated virus delivery of SOF (AAV SOF ) normalizes plasma and tissue FC accretion and reverses the pathologies associated with Scarb1 -/- mice. Methods: The lipid compositions of plasma, HDL, erythrocytes, and tissues of Scarb1 -/- mice treated with AAV SOF at 12-13 weeks of age for three weeks were compared with age- and sex-matched wild type (WT) C57BL6 and Scarb1 -/- mice. Results: As hypothesized, AAV SOF reduced plasma and HDL-FC and CE, as well as mol% FC in Scarb1 -/- mice towards WT levels. Erythrocyte FC levels also fell, but mol% FC remained elevated. Some changes were sex-specific: AAV SOF reduced the elevated FC only in female livers to WT levels. AAV SOF reduced FC and CE in lungs of females to WT levels, but not among males; the mol% FC remained high in both sexes. In steroidogenic tissues, adrenals, ovaries and testis, AAV SOF treatment increased FC. Unexpectedly, in Scarb1 -/- mice, AAV SOF increased mol% FC and FC in heart beyond already elevated levels. Conclusions: These findings support the hypothesis that plasma and HDL cholesterol levels determine tissue cholesterol levels that drive the pathologies specific to Scarb1 -/- mice. This evolving model of the role of HDL-FC in RCT provides a rationale for human studies to determine the utility of HDL-FC bioavailability as a risk factor for ASCVD and other pathologies.

Marginal Zinc Deficiency Alters Essential Fatty Acid Metabolism in Healthy Men

BackgroundRice biofortification with Zinc (Zn) can improve the Zn status of rice-consuming populations. However, the metabolic impact in humans consuming Zn-biofortified rice is unknown. ObjectivesTo determine the effects of Zn-biofortified rice on lipid metabolism in normolipidemic men. MethodsThe men consumed a rice-based diet containing 6 mg Zn/d and 1.5 g phytate (phytate/Zn ratio = 44) for 2 wk followed by a 10-mg Zn/d diet without phytate for 4 wk. An ad libitum diet supplemented with 25 mg Zn/d was then fed for 3 wk. Fasting blood samples were taken at baseline and at the end of each metabolic period for measuring plasma zinc, glucose, insulin, triglyceride (TG), LDL and HDL cholesterol, fatty acids, oxylipins, and fatty acid desaturase activities. Statistical differences were assessed by linear mixed model. ResultsFatty acid desaturase (FADS) 1 activity decreased by 29.1% (P = 0.007) when the 6-mg Zn/d diet was consumed for 2 wk. This change was associated with significant decreases in HDL and LDL cholesterol. The alterations in FADS1, HDL cholesterol, and TG remained unchanged when Zn intakes were increased to 10 mg/d for 4 wk. Supplementation with 25 mg Zn/d for 3 wk normalized these metabolic changes and significantly increased LDL cholesterol at the end of this metabolic period compared with baseline. FADS1 activity was inversely correlated with FADS2 (rmcorr = –0.52; P = 0.001) and TG (rmcorr = –0.55; P = 0.001) at all time points. ConclusionsA low-zinc, high-phytate rice-based diet reduced plasma HDL cholesterol concentrations and altered fatty acid profiles in healthy men within 2 wk. Consuming 10 mg Zn/d without phytate for 4 wk did not improve the lipid profiles, but a 25-mg Zn/d supplement corrects these alterations in lipid metabolism within 3 wk.

Sex-dependent relationship of C-reactive protein levels with HDL-cholesterol and HDL-phospholipid concentrations in children

Obesity has been consistently associated with inflammation but the influence of HDL on this association remains under study. Our study analyzes the influence of obesity-related parameters in the relationship of high-sensitivity C-reactive protein (hs-CRP) with HDL-cholesterol and HDL-phospholipid in male and female adolescents. The study sample population comprised 350 males and 401 females aged 12 to 16 years. Information regarding anthropometric parameters, HDL-cholesterol, HDL-phospholipid, adiponectin, leptin, insulin, and hs-CRP concentrations was available. hs-CRP levels were inversely related to HDL-cholesterol and HDL-phospholipid in males but not in females, and were positively related to leptin concentrations in both sexes but were not related to adiponectin levels. In regression analyses, HDL-phospholipid and leptin appeared significantly associated to hs-CRP in males in a model explaining 14.3% of hs-CRP variation. In females, only leptin appeared related to hs-CRP concentrations. After adjusting by leptin and adiponectin, males in the highest hs-CRP tertile showed significantly lower levels of HDL-cholesterol and HDL-phospholipid than those in tertiles 1 and 2, while no significant differences in HDL-cholesterol and HDL-phospholipid concentrations by hs-CRP tertile were observed in females. In summary, high hs-CRP levels were associated with lower plasma HDL-cholesterol and HDL-phospholipid concentrations in male adolescents irrespective of adipokines, while in females, HDL-related parameters are not associated with hs-CRP concentrations.

Impact of relative humidity on the laying performance, egg quality, and physiological stress responses of laying hens exposed to high ambient temperature.

The present study investigated the effects of relative humidity (RH) on the laying performance, egg quality, and stress indicators of laying hens raised at high ambient temperatures. A total of 180 Hy-Line Brown laying hens (68-wk-old) were randomly allotted to one of the following three RH conditions for 12h a day (9:00 a.m.-9:00 p.m.) over four weeks: low RH (LRH; 25% RH), moderate RH (MRH; 50% RH), and high RH (HRH; 75% RH); ambient temperature was 30°C under all treatments. None of the RH treatments affected hen-day egg production, egg weight, or egg mass (P>0.05). However, feed intake was lower in the HRH group than in the LRH group (P<0.05). Plasma corticosterone (CORT) concentration on day 21, yolk CORT concentration on day 3, and albumen CORT concentration on day 7 following RH exposure were higher in the HRH group than in the LRH group (P<0.05). Moreover, plasma HDL-cholesterol concentration on day 14 was higher in the HRH group than in the LRH group (P<0.05). On days 3 and 14, the Haugh unit decreased (P<0.05) in the LRH group compared with that in the MRH and HRH groups. The HRH-exposed laying hens showed the lowest (P<0.05) eggshell thickness on day 14. The absolute weights of eggshell, yolk, and albumen decreased in the HRH group compared with those in the MRH and LRH groups. Overall, high RH lowered feed intake and egg quality except for the Haugh unit, and induced stress response as manifested by elevated plasma, yolk, and albumen CORT concentrations. To our best knowledge, the present study is the first to demonstrate the role of RH in triggering temperature stress responses in laying hens.

In Vivo Effects of Coffee Containing Javamide-I/-II on Body Weight, LDL, HDL, Total Cholesterol, Triglycerides, Leptin, Adiponectin, C-Reactive Protein, sE-Selectin, TNF-α, and MCP-1

BackgroundDiet plays an unequivocal role in the development of obesity. Interestingly, recent studies have demonstrated that coffee products containing javamide-I/-II may be commonly found in the market. However, there is no information about in vivo effects of coffee containing javamide-I/-II (CCJ12) on obesity-related metabolic factors (body weight, LDL, HDL, total cholesterols, triglycerides, adiponectin, and leptin) in nonobese people. ObjectivesThe objective of this study was to investigate in vivo effects of CCJ12 on these metabolic factors as well as inflammatory/cardiovascular disease risk factors [C-reactive protein (CRP), soluble E-selectin (sE-selectin), TNF-α, monocyte chemoattractant protein-1 (MCP-1)] in a nonobese model. MethodsSprague-Dawley male rats were fed a complete diet for 20 wk with either drinking water containing CCJ12 [coffee containing javamide-I/-II group (CG), n = 10] or unsupplemented drinking water [water control group (NCG), n = 10]. The amounts of javamide-I/-II in CCJ12 were quantified by HPLC. Water/food consumption and body weight were monitored weekly, and the concentrations of metabolic/inflammatory/cardiovascular disease risk factors were measured by ELISA. ResultsThere was no significant difference in water/food consumption between the NCG and CG during the study. Also, no significant difference was found in average body weights between the groups either. In addition, after 20 wk, both groups did not show any significant difference in plasma LDL, HDL, and total cholesterol concentrations. Likewise, adiponectin and leptin concentrations were not significantly different between the groups. As expected, the 2 groups did not show any significant difference in plasma concentrations of CRP and sE-selectin. Furthermore, there was no significant difference in plasma concentrations of TNF-α and MCP-1 between the groups. ConclusionsThe data suggest that CCJ12 may not have significant effects on the metabolic/inflammatory/cardiovascular disease risk factors in the CG, compared with the NCG.

Abstract MP30: Excess HDL Free Cholesterol Bioavailability Drives Free Cholesterol Accretion Into Macrophages And Erythrocytes In Scarb1 -/- Mice

Aim: In humans, very high plasma HDL-cholesterol concentrations are associated with increased all cause- and atherosclerotic cardiovascular disease (ASCVD)-mortality. The HDL receptor-deficient mouse (Scarb1 -/- ), a robust model of this phenotype, is characterized by high free cholesterol (FC) bioavailability due to too many HDL particles that are FC-rich. Clinically, plasma LDL and HDL are quantified according to total cholesterol content, the sum of FC and esterified cholesterol, which likely contribute to ASCVD pathophysiology differently. A Western diet induces ASCVD in Scarb1 -/- mice, despite an attendant increase in HDL. We tested the hypothesis that high HDL-FC bioavailability contributes to ASCVD in Scarb1 -/- mice by increasing FC flux into macrophage cells, erythrocytes and other major tissues. Methods: Influx of HDL-FC and efflux of macrophage FC were determined between WT and Scarb1 -/- HDL and J774 macrophage cells. HDL of both genotypes were radiolabelled with [ 3 H]FC, injected into autologous mice, and the rates of plasma clearance and erythrocyte uptake were determined. Results: The magnitude of FC transfer from Scarb1 -/- HDL to LDL is greater than that from WT HDL; APOB-containing lipoproteins from Scarb1 -/- vs. WT mice are FC-enriched due likely to greater HDL-FC transfer. While macrophage efflux to HDL of Scarb1 -/- vs. WT HDL was not different, FC influx from Scarb1 -/- vs. WT HDL to macrophages was three-fold greater, a net effect that increased the FC burden of macrophages. In vivo studies showed that compared to WT mice, in Scarb1 -/- mice, autologous HDL-FC cleared more slowly and more FC transferred to erythrocytes. We compared the FC, CE, PL, and TG contents of all major tissues and determined that FC accretion by some tissues is higher among Scarb1 -/- vs. WT mice whereas in other tissues FC homeostasis is maintained. Lastly, we determined that the tissue compositions and plasma FC clearance kinetics varied according to sex, particularly among Scarb1 -/- mice. Conclusions: These findings are relevant to pathologies specific to Scarb1 -/- mice and to the evolving model of the role of HDL-FC in RCT. They provide a rationale for human studies to determine the utility of HDL-FC bioavailability as a risk factor for ASCVD and other pathologies.

Lower High-Density Lipoprotein Cholesterol Concentration Is Independently Associated with Greater Future Accumulation of Intra-Abdominal Fat.

BackgroundBoth intra-abdominal fat (IAF) and high-density lipoprotein cholesterol (HDL-C) are known to be associated with cardiometabolic health. We evaluated whether the accumulation of computed tomography (CT)-measured IAF over 5 years was related to baseline HDL-C concentration in a prospective cohort study.MethodsAll participants were Japanese-Americans between the ages of 34 and 74 years. Plasma HDL-C concentration and CT measurements of IAF, abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas were assessed at baseline and at 5-year follow-up visits.ResultsA total of 397 subjects without diabetes were included. The mean±standard deviation HDL-C concentration was 51.6±13.0 mg/dL in men and 66.0±17.0 mg/dL in women, and the IAF was 91.9±48.4 cm2 in men and 63.1±39.5 cm2 in women. The baseline plasma concentration of HDL-C was inversely associated with the change in IAF over 5 years using multivariable regression analysis with adjustment for age, sex, family history of diabetes, weight change over 5 years, and baseline measurements of body mass index, IAF, abdominal SCF, abdominal circumference, thigh SCF, and homeostatic model assessment for insulin resistance.ConclusionThese results demonstrate that HDL-C concentration significantly predicts future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in Japanese-American men and women without diabetes.

The rs508487, rs236911, and rs236918 Genetic Variants of the Proprotein Convertase Subtilisin-Kexin Type 7 (PCSK7) Gene Are Associated with Acute Coronary Syndrome and with Plasma Concentrations of HDL-Cholesterol and Triglycerides.

Dyslipidemia has a substantial role in the development of acute coronary syndrome (ACS). Previous reports, including genome-wide associations studies (GWAS), have shown that some genetic variants of the proprotein convertase subtilisin–kexin type 7 (PCSK7) gene are associated with plasma lipid levels. In the present study, we evaluated whether PCSK7 gene polymorphisms are significantly associated with the plasma lipid profile and ACS. Three PCSK7 gene polymorphisms (rs508487 T/C, rs236911 C/A, and rs236918 C/G) were determined using TaqMan genotyping assays in a group of 603 ACS patients and 622 healthy controls. The plasma lipid profile was determined in the study groups by enzymatic/colorimetric assays. Under the recessive model, the rs236918 C allele was associated with a high risk of ACS (OR = 2.11, pC = 0.039). In the same way, under the recessive and additive models, the rs236911 C allele was associated with a high risk of ACS (OR = 1.95, pC = 0.037, and OR = 1.28, pC = 0.037, respectively). In addition, under the co-dominant model, the rs508487 T allele was associated with a higher risk of ACS (OR = 1.78, pC = 0.010). The CCC and TCC haplotypes were associated with a high risk of ACS (OR = 1.21, pC = 0.047, and OR = 1.80, pC = 0.001, respectively). The rs236911 CC and rs236918 CC genotypes were associated with lower high-density lipoproteins-cholesterol (HDL-C) plasma concentrations, whereas the rs236911 CC genotype was associated with a higher concentration of triglycerides, as demonstrated in the control individuals who were not receiving antidyslipidemic drugs. Our data suggest that the PCSK7 rs508487 T/C, rs236911 C/A, and rs236918 C/G polymorphisms are associated with the risk of developing ACS, and with plasma concentrations of HDL-C and triglycerides.