High-density Lipoprotein Cholesterol Metabolism Research Articles

Relationship between physical activity and abdominal obesity and metabolic markers in postmenopausal women

This study aimed to investigate the impact of physical activity indicators monitored by the POLAR accelerometer on body obesity indicators, metabolic syndrome parameters, and energy metabolism hormones in postmenopausal women. Was included 71 participants from this study program (68.8 ± 4.3 years). We divided participants into LPA and MVPA groups based on their level of moderate to vigorous physical activity per week; Physical activity levels over 7 days were assessed using a POLAR accelerometer, with daily step counts and sedentary time recorded. Measurements included waist circumference, visceral fat volume, body fat percentage, blood pressure, fasting blood glucose, triglyceride levels, HDL cholesterol, and energy metabolism hormone levels (leptin, resistin, adiponectin). The MVPA group displayed lower waist circumference, body fat percentage, abdominal fat, and BMI compared to the LPA group (p < 0.05). A significant negative correlation was observed between daily step count and obesity indicators, including waist circumference (r = -0.301), body fat percentage (r = -0.295), abdominal fat (r = -0.318), and BMI (r = -0.238). Conversely, sedentary time showed a positive correlation with obesity indicators such as waist circumference (r = 0.258), body fat percentage (r = 0.239), and abdominal fat (r = 0.244). Moreover, daily step count exhibited a significant negative correlation with leptin levels (r = -0.245), while sedentary time was positively correlated with the energy metabolic factor leptin (r = 0.279). Waist circumference demonstrated significant positive correlations with triglycerides, blood glucose, adiponectin, resistin, and leptin levels. Postmenopausal women who engage in at least 150 min of MVPA weekly show lower obesity indices. There is a significant correlation between physical activity levels and obesity indicators, which relate to metabolic syndrome and energy metabolism factors. Thus, increased physical activity may help prevent metabolic syndrome and cardiovascular diseases in this population.

156-OR: Apolipoprotein C-II Posttranslational Truncation Is Associated with Reduced Incident Cardiovascular Risk in Multiethnic Study of Atherosclerosis (MESA)

Higher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I’/C-I) and C-II (C-II’/C-II) are associated with lower triglycerides (TG) and higher HDL levels. Here we examined the relationships of C-I’/C-II and C-II’/C-II, and total apo C-I and C-II concentrations with atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD). Apo C-I and C-II proteoforms were measured by mass spectrometry immunoassay at baseline in 5,765 MESA participants followed for CHD (definite myocardial infarction, resuscitated cardiac arrest or fatal CHD) and ASCVD (CHD or stroke) for up to 17 years. Baseline total apo C-I and C-II levels were measured in a subgroup of 3,848 participants. After adjusting for age, gender, and race/ethnicity, lower C-II’/C-II was associated with both ASCVD and CHD (Figure). The association of C-II’/C-II with CHD remained significant after further adjusting for BMI, diabetes, systolic BP, eGFR, use of tobacco, statins, antihypertensive medications, total apoC-II, and plasma TG, but was abolished after adjusting for HDL. Neither ASCVD nor CHD were related to total apo C-I and C-II or CI’/CI. In conclusion, increased posttranslational apoC-II truncation (but not total apo C-I or C-II) is associated with reduced cardiovascular risk, possibly explained by differences in HDL cholesterol metabolism. Disclosure J.Koska: None. J.Furtado: Employee; Biogen. Y.Hu: None. D.Nedelkov: None. D.Billheimer: Advisory Panel; AstraZeneca. M.Budoff: Research Support; Novo Nordisk, Novartis, Boehringer Ingelheim Inc., Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. M.Allison: None. R.Mcclelland: None. P.Reaven: Research Support; Dexcom, Inc. Funding National Heart, Lung, and Blood Institute (R01HL138969, 75N92020D00001, HHSN268201500003I, N01HC95159, 75N92020D00005, N01HC95160, 75N92020D00002, N01HC95161, 75N92020D00003, N01HC95162, 75N92020D00006, N01HC95163, 75N92020D00004, N01HC95164, 75N92020D00007, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169); National Center for Advancing Translational Sciences (UL1TR000040, UL1TR001079, UL1TR001420)

Mechanism of the Regulation of Plasma Cholesterol Levels by PI(4,5)P2.

Elevated low-density lipoprotein (LDL) cholesterol (LDLc) is one of the most well-established risk factors for cardiovascular disease, while high levels of high-density lipoprotein (HDL) cholesterol (HDLc) have been associated with protection from cardiovascular disease. Cardiovascular disease remains one of the leading causes of death worldwide; thus it is important to understand mechanisms that impact LDLc and HDLc metabolism. In this chapter, we will discuss molecular processes by which phosphatidylinositol-(4,5)-bisphosphate, PI(4,5)P2, is thought to modulate LDLc or HDLc. Section 1 will provide an overview of cholesterol in the circulation, discussing processes that modulate the various forms of lipoproteins (LDL and HDL) carrying cholesterol. Section 2 will describe how a PI(4,5)P2 phosphatase, transmembrane protein 55B (TMEM55B), impacts circulating LDLc levels through its ability to regulate lysosomal decay of the low-density lipoprotein receptor (LDLR), the primary receptor for hepatic LDL uptake. Section 3 will discuss how PI(4,5)P2 interacts with apolipoprotein A-I (apoA1), the key apolipoprotein on HDL. In addition to direct mechanisms of PI(4,5)P2 action on circulating cholesterol, Sect. 4 will review how PI(4,5)P2 may indirectly impact LDLc and HDLc by affecting insulin action. Last, as cholesterol is controlled through intricate negative feedback loops, Sect. 5 will describe how PI(4,5)P2 is regulated by cholesterol.

Portulaca oleracea L. Extract Regulates Hepatic Cholesterol Metabolism via the AMPK/MicroRNA-33/34a Pathway in Rats Fed a High-Cholesterol Diet.

This study examined the effect of extruded Portulaca oleracea L. extract (PE) in rats fed a high-cholesterol diet through the AMP-activated protein kinase (AMPK) and microRNA (miR)-33/34a pathway. Sprague–Dawley rats were randomized into three groups and fed either a standard diet (SD), a high-cholesterol diet containing 1% cholesterol and 0.5% cholic acid (HC), or an HC diet containing 0.8% PE for 4 weeks. PE supplementation improved serum, liver, and fecal lipid profiles. PE upregulated the expression of genes involved in cholesterol efflux and bile acids’ synthesis such as liver X receptor alpha (LXRα), ATP-binding cassette subfamily G5/G8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1), and downregulated farnesoid X receptor (FXR) in the liver. In addition, hepatic gene expression levels of apolipoprotein A-l (apoA-1), paraoxonase 1 (PON1), ATP-binding cassette subfamily A1/G1 (ABCA1/G1), lecithin-cholesterol acyltransferase (LCAT), and scavenger receptor class B type 1 (SR-B1), which are related to serum high-density lipoprotein cholesterol metabolism, were upregulated by PE. Furthermore, hepatic AMPK activity in the PE group was higher than in the HC group, and miR-33/34a expression levels were suppressed. These results suggest that PE improves the cholesterol metabolism by modulating AMPK activation and miR-33/34a expression in the liver.

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.

Methylsulfonylmethane and Sesame Seed Oil Improve Dyslipidemia and Modulate Polyunsaturated Fatty Acid Metabolism in Two Mouse Models of Diabetes.

The objective of this study was to identify alterations in lipids and polyunsaturated fatty acid (PUFA) metabolism in both the streptozotocin (STZ)-induced type 1 diabetic (T1D) mouse and the mutant db/db type 2 diabetic (T2D) mouse to establish a biological signature for the evaluation of natural products with purported lipid-altering activity. Eight-week-old male C57BL/6J mice were randomized to nondiabetic group or STZ-induced diabetic groups (n = 10/group). STZ-induced diabetic mice and 6-week-old male db/db mice (n = 10/group) were randomized to the following groups: (1) diabetic control, no treatment, (2) methylsulfonylmethane (MSM) treatment, (3) sesame seed oil (SSO) treatment, and (4) MSM+SSO combination treatment. Clinical parameters measured included weights, blood glucose, serum lipid panels, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of free fatty acids in serum, liver, brain, and eyes. Blood glucose significantly decreased after 4 weeks of MSM treatment in T1D mice. Serum PUFA levels were significantly reduced in T2D mice compared with control mice. In contrast, treatment with SSO reversed this effect in T2D mice, exhibiting serum PUFA levels comparable to control mice. Serum triglycerides were significantly increased in both diabetic models compared to nondiabetic control, mimicking diabetes in people. High-density lipoprotein (HDL) was significantly increased in T1D receiving MSM+SSO and all T2D treatment groups. A corresponding significant decrease in non-HDL cholesterol was seen in T2D mice in all treatment groups. MSM+SSO treatment's effects on HDL and non-HDL cholesterol and PUFA metabolism could lead to improved clinical outcomes in diabetics by improving the lipid profile.

The Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism.

ContextBlood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive.ObjectiveHere, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism.MethodsWe elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status.ResultsA lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels.ConclusionTaken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Cholesterol metabolism related genes in osteoarthritis.

Cholesterol homeostasis plays a significant role in skeletal development and the dysregulation of cholesterol-related mechanism has been shown to be involved in the development of cartilage diseases including osteoarthritis (OA). Epidemiological studies have shown an association between elevated serum cholesterol levels and OA. Furthermore, abnormal lipid accumulation in chondrocytes as a result of abnormal regulation of cholesterol homeostasis has been demonstrated to be involved in the development of OA. Although, many in vivo and in vitro studies support the connection between cholesterol and cartilage degradation, the mechanisms underlying the complex interactions between lipid metabolism, especially HDL cholesterol metabolism, and OA remain unclear. The current review aims to address this problem and focuses on key molecular players of the HDL metabolism pathway and their role in ΟΑ pathogenesis. Understanding the complexity of biological processes implicated in OA pathogenesis, such as cholesterol metabolism, may lead to new targets for drug therapy of OA patients.

367Association between dietary fatty acid intake, serum levels of fatty acids and ABCA1 DNA methylation

Abstract Background Although previous studies have demonstrated that n-3 polyunsaturated fatty acids (PUFA) are inversely associated with a risk of CVD through gene expression, recent evidence suggests that it may arise from changes in DNA methylation. Therefore, we investigated whether dietary FA intake and serum FA levels are associated with ATP-binding cassette transporter A1 (ABCA1), a gene associated with HDL-cholesterol metabolism. Methods A total of 298 subjects (137 men, mean age of 63.2) without clinical history and medication participated in this cross-sectional study. We used the pyrosequencing method to measure DNA methylation levels at 8 CpG sites within ABCA1 gene and calculated mean DNA methylation level. Dietary FA intake were assessed with the food frequency questionnaire. Results We found that ABCA1 DNA methylation levels were significantly lower with higher dietary intake of n-3PUFA (β = –5.75, p = 0.001), which is observed both in men (β = –4.85, p = 0.001) and women (β = –7.24, p = 0.007). In addition, ABCA1 DNA methylation levels were significantly lower with higher serum levels of n-3PUFA in men (β = –2.78, p = 0.05), but not in women (β = 1.61, p = 0.31). Conclusions The results suggest that higher dietary n-3 PUFA intake and serum levels of n-3 PUFA are associated with lower ABCA1 DNA methylation in a Japanese population. Key messages Higher dietary n-3 PUFA intake can be a prevention from dyslipidemia and CVD via low level of ABCA1 DNA methylation

Relationship between COVID-19 and HDL dysfunction

Recent data show that no age group is excluded from the possibility of SARS-CoV-2 infection. However, it is more likely to affect the elderly with comorbidities such as cardiovascular and pulmonary diseases, diabetes, and hypertension that can lead to the progression of COVID-19. Dyslipidemia is often found with these comorbid diseases. According to recent findings, lipoproteins, and particularly high- density lipoprotein cholesterol (HDL-C), may play a role in regulating the entry of the SARS-CoV-2 virus into the host cell. In fact, HDL-C has many beneficial properties, including anti-inflammatory, anti-oxidative, anti-thrombotic, anti-infectious, anti-apoptotic, intercellular communication, and pro-vasodilator capacities. HDL-C has an affinity for binding and neutralization of the pathogen. The link between COVID-19 and lipid-dependent pathologies has not yet been fully understood. We draw attention to the molecules and functions involved in HDL-C. Because many therapeutic compounds that regulate HDL-C functions and metabolism can be used in the treatment of COVID-19 recently.

Suppression of serum lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism by intensive insulin therapy in the first year of type 1 diabetes mellitus: Prospective InLipoDiab1 study

Background and aimsCholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are crucial proteins in reverse cholesterol transport. There are insufficient data on regulating these proteins by insulin therapy in type 1 diabetes mellitus (T1DM). We aimed to assess prospectively the impact of insulin therapy initiation on transfer proteins serum levels in adults with newly diagnosed T1DM. Methods and results57 adults with newly diagnosed T1DM were enrolled in the InLipoDiab1 Study. All participants were treated with subcutaneous insulin in the model of intensive insulin therapy since the diagnosis of diabetes. Serum PLTP and CETP concentrations were measured at diagnosis, after three weeks, six months, and after one year of insulin treatment, using the immunoenzymatic method ELISA.A significant decrease in PLTP and CETP concentrations were demonstrated during twelve months of insulin therapy in newly diagnosed T1DM. The dynamics of changes in the level of these proteins varied depending on the occurrence of remission after a year of the disease. In the group without remission, a significant decrease in PLTP and CETP levels appeared after six months of follow-up. The remission group was characterized by a decrease in proteins concentration only after one year of treatment. In the non-remission group, significant negative correlations were found between the daily dose of insulin and levels of PLTP and CETP. ConclusionExogenous insulin is an inhibitor of lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism in the first year of treatment.

Study of the relationship between endothelial lipase gene polymorphism and serum levels of HDL-C, Apo A-I and severity of stenosis in non-diabetic coronary artery disease patients

BackgroundThe endothelial lipase (EL) gene is one of the most important genes in the metabolism of high-density lipoprotein cholesterol (HDL-C), and then it may be involved in the pathogenesis of coronary artery disease (CAD). The present study aimed to reveal the potential relationship between the EL 584C/T gene polymorphism and CAD severity, serum apolipoprotein A-I (Apo A-I), Apo B, and HDL-C levels in non-diabetic CAD patients. Methods248 subjects including 89 non-CAD controls and 159 non-diabetic CAD patients were included in the study. Blood sample was collected and used for genomic DNA extraction. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was carried out for genotyping of EL 584C/T. Serum levels of Apo A-I and Apo B were determined using the immunoturbidometric assay. The severity of coronary stenosis was determined using the Gensini score (GS). ResultsThe frequency of CC genotype was 52.9% and the frequency of CT and TT genotypes was 47.1% in non-CAD group. These frequencies were 59.6% and 40.4% in CAD group, respectively. There was no significant difference in the frequency of 584C/T polymorphism between CAD and non-CAD group. Moreover, the genotype and allele frequencies of the 584C/T polymorphism were not statistically different in subjects with different degrees of coronary stenosis. The serum level of Apo A-I was markedly increased in non-CAD group rather than CAD group. Those subjects with TT and CT genotypes had significantly higher levels of Apo A-I compared to those with CC genotype. ConclusionOur results showed that 584C/T polymorphism of the EL gene was not associated with the risk of CAD. However, subjects with TT and CT genotypes showed higher Apo A-I levels compared to subjects with CC genotype suggesting a possible role of these genotype in the pathogenesis of CAD.

HDL-apoA-I kinetics in response to 16 wk of exercise training in men with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise (n = 15), or conventional lifestyle advice (n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8-32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P < 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6-36.1% to 8.9% (4.4-17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG.

Cholesterol membrane content has a ubiquitous evolutionary function in immune cell activation: the role of HDL.

Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes. The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach. Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology.

Modulation of cholesterol efflux capacity in patients with myocardial infarction

Epidemiologic studies consistently demonstrated that patients with coronary artery disease (CAD) and low HDL cholesterol (HDL-C) are more likely to develop major adverse cardiovascular events as compared with those with normal or high HDL. However, several large randomized trials failed to demonstrate that a substantial, pharmacological-based, increase of HDL-C concentrations results in a clinically significant reduction of ischemic outcomes. This has been largely attributed to the fact that, although these drugs are able to raise the HDL-C concentration, they have no effect on HDL-C atheroprotective function. Subsequently, the 'HDL hypothesis' evolved, and the focus shifted from raising the concentration of HDL-C to raising the reverse cholesterol transport (RCT) function by increasing patients cholesterol efflux capacity (CEC) instead. Indeed, new data suggest that HDL-C metabolism and the ability of the HDL molecule to transport cholesterol from the atherosclerotic plaque to the liver, measured by the CEC, is more important than steady-state HDL-C levels. Modulation of the CEC has become, therefore, a promising therapeutic target in CAD patients. This article reviews the current data on the 'cholesterol efflux hypothesis' and discuss its ability to be modulated has a potential therapeutic target. Recent data have demonstrated that impaired serum CEC was associated with increased mortality after a myocardial infarction (MI). Thus, therapeutic intervention aiming to improve CEC and RCT may reduce the risk of recurrent events. Early phase clinical studies targeting CEC showed promising results and a megatrial is ongoing testing the hypothesis that an improved RCT trough a modulation of the CEC can modify patient's prognosis after an acute MI. The 'cholesterol efflux hypothesis' is now supported by several clinical studies and is being tested with a therapeutic candidate in a megatrial enrolling high-risk patient with MI.

Associations between dietary vitamin intake, ABCA1 gene promoter DNA methylation, and lipid profiles in a Japanese population

Higher intake of fruits and vegetables is associated with reduced risk of specific types of cancer and of cardiovascular disease (CVD), but the protective role of the vitamins contained in fruits and vegetables on CVD is controversial. This discrepancy can raise the question of the effects of antioxidants in vitamins on CVD. Recently, we reported that higher vegetable intake was significantly associated with the decreased DNA methylation level of ATP-binding cassette transporter A1 (ABCA1), a gene associated with HDL-cholesterol metabolism. We investigated whether ABCA1 DNA methylation mediates an effect of dietary vitamin intake on lipid profiles, an important risk factor for CVD, in a Japanese population. A total of 225 individuals (108 men and 117 women) with no clinical history and no drug use for dyslipidemia participated in this cross-sectional study. We used the pyrosequencing method to measure the ABCA1 DNA methylation levels at 8 CpG sites, and we used mean DNA methylation level in statistical analysis. Dietary vitamin intake was assessed with the FFQ and adjusted for the residual method. In women, higher dietary vitamin intake [vitamin A, β-carotene, folic acid, vitamin C (VC), vitamin D, and vitamin E] was significantly associated with lower mean ABCA1 DNA methylation levels (P=0.004, 0.03, 0.005, 0.001, 0.03, and 0.04, respectively). In addition, in women, we found a significant inverse association between mean ABCA1 DNA methylation and HDL cholesterol (P=0.04) but not for other lipid indexes. Mediation analysis showed a significant indirect effect of VC intake on HDL cholesterol through ABCA1 DNA methylation level in women (P=0.04). Although this study does not prove causality, the results suggest that ABCA1 DNA methylation mediates the protective effect of VC on HDL cholesterol in women, which could offer a novel biological mechanism in CVD prevention.

The role of free triiodothyronine in high-density lipoprotein cholesterol metabolism.

The aim of this study was to analyze the correlation between free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and serum high-density lipoprotein cholesterol (HDL-C), and to explore the significance of FT3 in HDL-C metabolism in people with normal thyroid function.A total of 461 Chinese, aged ≥28 years, from a college community in Nanning, Guangxi, were enrolled for a cross-sectional epidemiological investigation of metabolic syndrome from October 2016 to November 2016. Height, weight, blood pressure, total cholesterol, HDL-C, triglyceride (TG), fasting glucose (FPG), FT3, FT4, and TSH were measured for each individual. Multiple linear regression analysis was used to evaluate the correlation between FT3, FT4, TSH, and HDL-C.After controlling for sex, age, body mass index (BMI), smoking, drinking, and other confounding factors, FT3 was negatively correlated with HDL-C levels, on average, when FT3 increased by 1 pmol/L, HDL-C decreased by 0.143 mmol /L with a statistically significant difference (P < .001). FT4 was positively correlated with HDL-C, and HDL-C increased by 0.016 mmol/L for every 1-pmol/L increase in FT4. TSH was negatively correlated with HDL-C, and HDL-C decreases by 0.010 mmol/L for every 1-μIU/mL increase in TSH, but the differences were not statistically significant (P > .05).FT3 may be an important factor affecting HDL-C levels. The detection and regulation of thyroid hormone (especially FT3) in patients with low HDL-C, as well as the detection of HDL-C in patients with thyroid dysfunction, is important to prevent the occurrence of cardiovascular diseases.

Longitudinal lipid trends and adverse outcomes in patients with CKD: a 13-year observational cohort study

Studies on the effects of longitudinal lipid trajectories on end-stage renal disease (ESRD) development and deaths among patients with chronic kidney disease (CKD) are limited. We conducted a registry-based prospective study using data from a 13-year multidisciplinary pre-ESRD care program. The final study population comprised 4,647 patients with CKD. Using group-based trajectory modeling, we dichotomized longitudinal trajectories of total cholesterol (T-CHO), triglyceride (TG), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C). Time to ESRD or death was analyzed using multiple Cox regression. At baseline, higher levels of T-CHO and LDL-C were associated with rapid progression to ESRD, whereas only HDL-C was positively associated with all-cause mortality [adjusted hazard ratio (HR), 1.20; 95% CI, 1.06-1.36; P-value, 0.005]. Compared with those with a normal T-CHO trajectory, the fully adjusted HR of patients with a high T-CHO trajectory for ESRD risk was 1.21 (P-value, 0.019). Subgroup analysis showed that a high TG trajectory was associated with a 49% increase in mortality risk in CKD patients without diabetes (P-value for interaction, 0.012). In contrast to what was observed based on baseline HDL-C, patients with a trajectory of frequent hypo-HDL cholesterolemia had higher risk of all-cause mortality (adjusted HR, 1.53; P-value, 0.014). Thus, only T-CHO, both at baseline and over the longitudinal course, demonstrated a significant potential risk of incident ESRD. The inconsistency in the observed directions of association between baseline levels and longitudinal trajectories of HDL-C warrants further research to unveil specific pathogenic mechanisms underlying the HDL-C metabolism in patients with CKD.

Decreased serum levels of CTRP12/adipolin in patients with coronary artery disease in relation to inflammatory cytokines and insulin resistance

Coronary artery disease (CAD) is the leading cause of death worldwide. Atherosclerosis as the main underlying mechanism of CAD is associated with inflammation and adipose tissue dysfunction. C1q/TNF-related protein12 (CTRP12) is a newly discovered adipokine which is a paralog of adiponectin. CTRP12 has anti-inflammatory and insulin sensitizing effects. Circulating levels of this adipokine have been reported to be lower in patients with type 2 diabetes and women with polycystic ovarian syndrome. The present study was undertaken for the first time to evaluate serum levels of CTRP12 in CAD patients and its association with anthropometric and biochemical parameters.Serum levels of CTRP12 were measured using ELISA kit in 188 CAD patients (angiography confirmed) and 70 controls. The serum levels of adiponectin, TNF-α and IL-6 were measured using ELISA kits.Serum levels of CTRP12 were found to be lower in CAD patients (585.48 ± 201.67 pg/mL) than in the controls (814.86 ± 247.85 pg/mL; p < 0.001). CTRP12 also showed an independent association with the risk of CAD (OR [CI] = 0.998 [0.996–0.999]; p = 0.019). Moreover, it showed an inverse correlation with HOMA-IR (r = −0.298; p = 0.012) and TNF-α (r = −0.269; p = 0.023) and a positive correlation with adiponectin (r = 0.344; p = 0.003) in the controls. In CAD patients, CTRP12 was inversely correlated with BMI (r = −0.181, p = 0.013), HOMA-IR (r = -0.199; p = 0.006), TNF-α (r = -0.259; p < 0.001) and IL-6 (r = -320; p < 0.001) and a positive correlation with high density lipoprotein-cholesterol(r = 0.342; p < 0.001) and adiponectin (r = 0.398; p < 0.001).The present study showed for the first time that serum levels of CTRP12 are independently associated with CAD and that CTRP12 is associated with several CAD risk factors. The results suggest a possible link between CTRP12 and pathogenic mechanisms of atherosclerosis, such as inflammation and high density lipoprotein-cholesterol metabolism; however, more study is required in this regard.

MicroRNA‐146a Deficiency Promotes Atherosclerosis by Dysregulating Cholesterol Homeostasis in Macrophages

Atherosclerosis is a chronic inflammatory disease that results from imbalance of high‐density lipoprotein (HDL) cholesterol metabolism and a maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the artery wall. MicroRNA‐146a (miR‐146a) serves as anti‐inflammatory function in a variety of cell types, but the underlying mechanisms of miR‐146a in atherosclerosis still remain unclear. In the present study, we assessed the impact of the genetic deficiency of miR‐146a in a mouse model of atherosclerosis and determined the miR‐146a‐mediated balance of cholesterol metabolism in macrophages. In comparison with miR‐146a+/+ApoE−/− mice fed with high‐cholesterol diet for 10 weeks, miR‐146a−/−ApoE−/− mice showed an increase number and area of atherosclerotic plaques, lipid content, pro‐inflammatory cytokines and abundant macrophages accumulated in the plaques. In addition, miR‐146a−/−ApoE−/− mice also showed decrease in HDL levels. Bone marrow chimera experiments indicated a major effect of miR‐146a deficiency on lesional macrophages. Bone marrow derived‐macrophages (BMDMs) were isolated from miR‐146a−/−ApoE−/− and miR‐146a+/+ApoE−/− mice to stimulated with oxidized low‐density lipoprotein (oxLDL). In comparison with BMDMs of miR‐146a+/+ApoE−/−, BMDMs of miR‐146a−/−ApoE−/− showed a significant oxLDL uptake and reduction in cholesterol efflux capacity. The expression of cholesterol transporters, including the ATP‐binding cassette sub‐family A1 (ABCA1) and sub‐family G1 (ABCG1) were significantly decreased in BMDMs of miR‐146a−/−ApoE−/−. By using the global gene expression analysis and argonaute‐2 immunoprecipitation, we demonstrated that toll‐like receptor 4 (TLR4) is directly targeted by miR‐146a. Overexpression of miR‐146a and silence of TLR4 not only increased the expression of ABCA1 and ABCG1, but also increased the cholesterol efflux capacity and reduced the oxidized LDL uptake. These data demonstrated that miR‐146a is involved in regulation of ABCA1 and ABCG1 by targeting TLR4, and that maintains the balance of HDL cholesterol metabolism to protect against the atherosclerosis. MiR‐146a is a potential target in treatment of atherosclerotic vascular disease.Support or Funding InformationMOST 104‐2321‐B‐400‐020‐MY3 (to L.‐J. C.) and MOST 104‐2321‐B‐400‐017 (to J.‐J. C.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.