Comprehensive meta-analysis of the effects of oral medroxyprogesterone acetate plus conjugated equine oestrogens on the lipid profile in women: Insights from randomized controlled trials.

BACKGROUND: Menopause is associated with elevated cardiovascular risk due to the loss of the cardioprotective effect of oestrogens. Postmenopausal women are often prescribed hormone replacement therapy (HRT) in order to control menopause symptoms and correct hormone imbalances; however, HRT can impact serum lipids' concentrations. At present, data on the effect of the administration of medroxyprogesterone acetate plus conjugated equine oestrogens (MPACEE) on the lipid profile in females are uncertain, as the investigations conducted so far have produced conflicting results. Thus, we aimed to clarify the impact of MPACEE prescription on the serum lipids' values in women by means of a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We employed a random-effects model based on the DerSimonian and Laird method to determine the combined estimates of the intervention's impact on the lipid profile. The computation of the weighted mean difference (WMD) and its corresponding 95% confidence interval (CI) relied on the mean and standard deviation values from both the MPACEE and control group, respectively. RESULTS: A total of 53 RCTs were included in the meta-analysis with 68 RCT arms on total cholesterol (TC), 70 RCT arms on low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and 69 RCT arms on high-density lipoprotein cholesterol (HDL-C). Administration of MPACEE resulted in a significant reduction of TC (WMD = -11.93 mg/dL; 95% CI: -13.42, -10.44; p < .001) and LDL-C (WMD = -16.61 mg/dL; 95% CI: -17.97, -15.26; p < .001) levels, and a notable increase in HDL-C (WMD = 3.40 mg/dL; 95% CI: 2.93, 3.86; p < .001) and TG (WMD = 10.28 mg/dL; 95% CI: 7.92, 12.64; p < .001) concentrations. Subgroup analysis revealed that changes in the lipid profile were influenced by several factors: body mass index (for TC, HDL-C, TG), MPACEE dosages (for TC, LDL-C, HDL-C, TG), age (for TC, LDL-C, HDL-C, TG), durations of the intervention (for TC, LDL-C, HDL-C, TG), continuous/sequential administration of MPACEE (continuous for TC; sequential for LDL-C, TG) administration of MPACEE and serum lipids' concentrations before enrolment in the RCT (for TC, LDL-C, HDL-C, TG). CONCLUSIONS: MPACEE administration can influence serum lipids' concentrations in females by raising HDL-C and TG levels and reducing LDL-C and TC values. Therefore, postmenopausal women who suffer from hypercholesterolaemia might benefit from this type of HRT.

Efficacy and Safety of Pemafibrate Versus Bezafibrate to Treat Patients with Hypertriglyceridemia: A Randomized Crossover Study.

AIM: Pemafibrate is a highly selective agonist for peroxisome proliferator-activated receptor (PPAR)-α, a key regulator of lipid and glucose metabolism. We compared the efficacy and safety of pemafibrate with those of bezafibrate, a nonselective PPAR-α agonist. METHODS: In this randomized crossover study, 60 patients with hypertriglyceridemia (fasting triglyceride [TG] ≥ 150 mg/dL) were treated with pemafibrate of 0.2 mg/day or bezafibrate of 400 mg/day for 24 weeks. The primary endpoint was percent change (%Change) from baseline in TG levels, while the secondary endpoints were %Change in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (Apo A-I) levels. RESULTS: The %Change in TG and Apo A-I levels was significantly greater with pemafibrate than with bezafibrate (-46.1% vs. -34.7%, p＜0.001; 9.2% vs. 5.7%, p =0.018, respectively). %Change in HDL-C levels was not significantly different between the two treatments. %Change in liver enzyme levels was markedly decreased with pemafibrate than with bezafibrate. Creatinine levels significantly increased in both treatments; however, its %Change was significantly lower with pemafibrate than with bezafibrate (5.72% vs. 15.5%, p＜0.001). The incidence of adverse events (AEs) or serious AEs did not differ between the two treatments; however, the number of patients with elevated creatinine levels (≥ 0.5 mg/dL and/or 25% from baseline) was significantly higher in the bezafibrate group than in the pemafibrate group (14/60 vs. 3/60, p =0.004) [corrected]. CONCLUSION: Compared with bezafibrate, pemafibrate is more effective in decreasing TG levels and increasing Apo A-I levels and is safer regarding liver and renal function.

Effects of dietary eicosapentaenoic acid and docosahexaenoic acid supplementation on metabolic syndrome: A systematic review and meta-analysis of data from 33 randomized controlled trials.

BACKGROUND & AIMS: Previous randomized controlled trials (RCTs) have compared the effects of pure preparations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in reducing metabolic syndrome (MetS) risk factors, but the results were inconsistent. The present study aimed to clarify whether EPA and DHA have differential effects on MetS features in humans. METHODS: A systematic literature search was conducted in CNKI, PubMed, Embase and Scopus updated to February 2021. The mean changes in the characteristics of MetS were calculated as weighted mean differences by using a random-effects model. Thirty-three RCTs were included. RESULTS: The results showed that both EPA and DHA were effective at lowering serum triglycerides (TG) levels. EPA supplementation decreased the serum levels of total cholesterol (TC) (WMD = -0.24 mmol/L; 95% CI, -0.43, -0.05 mmol/L), TG (WMD = -0.77 mmol/L; 95% CI, -1.54, -0.00 mmol/L) and low density lipoprotein-cholesterol (LDL-C) (WMD = -0.13 mmol/L; 95% CI, -0.25, -0.01 mmol/L), while DHA increased the serum levels of TC (WMD = 0.14 mmol/L; 95% CI, 0.03, 0.25 mmol/L), LDL-C (WMD = 0.26 mmol/L; 95% CI, 0.15, 0.38 mmol/L) and high density lipoprotein-cholesterol (HDL-C) (WMD = 0.07 mmol/L; 95% CI, 0.04, 0.09 mmol/L). Moreover, DHA increased the serum levels of insulin compared with EPA, especially in subgroups whose mean age was <60 years (0.43 mU/L; 95% CI: 0.04, 0.81 mU/L) and duration of DHA supplementation < 3 months (0.39 mU/L; 95% CI: 0.01, 0.77 mU/L). CONCLUSIONS: The present meta-analysis provides evidence that EPA and DHA have different effects on risk factors of MetS.

Maternal exposure of mice to sodium p-perfluorous nonenoxybenzene sulfonate causes endocrine disruption in both dams and offspring.

The toxicity of certain novel perfluoroalkyl substances (PFCs) has attracted increasing attention. However, the toxic effects of sodium p-perfluorous nonenoxybenzene sulfonate (OBS) on the endocrine system have not been elucidated. In this study, OBS was added to the drinking water during the pregnancy and lactation of the healthy female mice at dietary levels of 0.0 mg/L (CON), 0.5 mg/L (OBS-L), and 5.0 mg/L (OBS-H). OBS exposure during the pregnancy and lactation resulted in the presence of OBS residues in the placenta and fetus. We also analyzed physiological and biochemical parameters and gene expression levels in mice of the F0 and F1 generations after maternal OBS exposure. The total serum cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly increased in female mice of the F0 generation. The androgen levels in the serum and the ovarian mRNA levels of androgen receptor (AR) also tended to increase after maternal OBS exposure in the F0 generation mice. Moreover, maternal OBS exposure altered the mRNA expression of endocrine-related genes in male mice of F1 generation. Notably, the serum TC and LDL-C levels were significantly increased in 8-weeks-old male mice of the F1 generation, and the serum high-density lipoprotein cholesterol (HDL-C) levels were decreased in 24-week-old male mice of the F1 generation. These results indicated that maternal OBS exposure can interfere with endocrine homeostasis in the F0 and F1 generations. Therefore, exposure to OBS during pregnancy and lactation has the potential toxic effects on the dams and male offspring, which cannot be overlooked.

Comparison of metabolic effects of the progestational androgens dimethandrolone undecanoate and 11ß-MNTDC in healthy men.

BACKGROUND: Dimethandrolone (DMA) and 11ß-methyl-19-nortestosterone (11ß-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men. OBJECTIVE: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens. MATERIALS/METHODS: In two clinical trials of DMA undecanoate (DMAU) and 11ß-MNT dodecylcarbonate (11ß-MNTDC), oral prodrugs of DMA and 11ß-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo. RESULTS: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11ß-MNTDC. An increase in LDL-C was seen with 11ß-MNTDC but not with DMAU. DISCUSSION: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies. CONCLUSION: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds.

The efficacy of novel metabolic targeted agents and natural plant drugs for nonalcoholic fatty liver disease treatment: A PRISMA-compliant network meta-analysis of randomized controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis. METHODS: Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed. RESULTS: Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels. CONCLUSIONS: Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.

Effects of different delivering matrices of ß-glucan on lipids in mildly hypercholesterolaemic individuals: a meta-analysis of randomised controlled trials.

ß-Glucan has been reported for its health benefits on blood lipids in hypercholesterolaemic individuals for years. However, people have paid little attention to the effects of ß-glucan in populations with mild hypercholesterolaemia as well as the various delivering matrices. Our objective was to perform a meta-analysis to analyse the effects of ß-glucan with different delivering matrices in mildly hypercholesterolaemic individuals. After conducting a comprehensive search in Web of Science, PubMed, Scopus and Cochrane Library, a total of twenty-one randomised controlled trials involving 1120 participants were identified to measure the pooled effect. The overall results indicated that consuming a dose of ≥3 g/d of ß-glucan for at least 3 weeks could significantly reduce total cholesterol (TC) (-0·27 mmol/l, 95 % CI -0·33, -0·21, P < 0·001) and LDL-cholesterol (-0·26 mmol/l, 95% CI -0·32, -0·20, P < 0·001) compared with the control group in mildly hypercholesterolaemic individuals, while no significant difference was observed in TAG (-0·03 mmol/l, 95% CI -0·11, 0·06, P = 0·521) and HDL-cholesterol (0·01 mmol/l, 95% CI -0·03, 0·04, P = 0·777). There was evidence for modest unexplained heterogeneity in the meta-analysis. In conclusion, ß-glucan can significantly reduce risk factors like TC and LDL-cholesterol for CVD in mildly hypercholesterolaemic individuals; furthermore, it appears that the effects of food matrices with both 'solid products' and 'liquid products' where ß-glucan was incorporated into were ranked as the best way to exert its beneficial properties, while 'liquid' and 'solid' products were ranked as the second and third positions, respectively.

Hydrogen influences HDL-associated enzymes and reduces oxidized phospholipids levels in rats fed with a high-fat diet.

AIMS: Oxidized phospholipids (OxPLs) are formed as a result of oxidative stress, which potentially mediate multiple pathological effects. We aimed to evaluate the effects of hydrogen (H2) on OxPLs in vivo and the underlying mechanism. MAIN METHODS: Rats were randomly assigned to three groups: control group fed with a chow diet, model group fed with a high-fat diet, and H2-treated group fed with a high-fat diet and treated by 4% H2 inhalation for ten weeks. OxPLs in liver and plasma were analyzed by liquid chromatography-mass spectrometry. High-density lipoprotein (HDL) was separated by ultracentrifugation. A proteomic analysis was performed to reveal the alternation of HDL protein composition and he antioxidant capacity of HDL was tested by low-density lipoprotein oxidation experiment. Furthermore, the activity or expression of HDL-associated enzymes were evaluated. KEY FINDINGS: Inhalation of 4% H2 decreased the accumulation of OxPLs in rats. In vitro tests revealed that the different concentrations of H2 did not inhibit the formation of OxPLs mediated by non-enzymatic oxidation. H2 inhalation altered the components and enhanced the anti-oxidative capacity of HDL in rats fed with a high-fat diet. Further experiments showed that H2 significantly regulated the activity of lipoprotein-associated phospholipase A2, paraoxonase-1, and the expression of lecithin:cholesterol acyltransferase. SIGNIFICANCE: Our findings revealed that H2 may reduce the OxPLs levels through its influence on HDL-associated enzymes that can act on OxPLs, suggesting that H2 can be used in alleviating diseases related to lipid peroxidation due to oxidative stress.

Effects of α-Cyclodextrin on Cholesterol Control and Hydrolyzed Ginseng Extract on Glycemic Control in People With Prediabetes: A Randomized Clinical Trial.

Importance: Effective strategies for preventing type 2 diabetes are needed. Many people turn to complementary medicines, but there is little well-conducted scientific evidence to support their use. Objective: To assess the efficacy of α-cyclodextrin for cholesterol control and that of hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Design, Setting, and Participants: This 6-month double-blind, placebo-controlled, randomized clinical trial, with a 2 × 2 factorial design, was conducted between July 2015 and October 2018 at 2 locations in Sydney, Australia. Eligible participants were aged 18 years or older, had a body mass index (weight in kilograms divided by height in meters squared) of 25 or higher, and had prediabetes within 6 months of study entry according to the American Diabetes Association guidelines. Data analysis was performed from May to August 2019. Interventions: Participants were randomized to 1 of 4 groups to take active or placebo versions of each supplement (α-cyclodextrin plus hydrolyzed ginseng, α-cyclodextrin plus placebo, placebo plus hydrolyzed ginseng, or placebo plus placebo) for 6 months. All participants received dietetic advice for weight loss. Main Outcomes and Measures: The primary outcomes were the differences in total cholesterol and fasting plasma glucose between groups after 6 months. The primary analysis used the intention-to-treat principle. Multiple predetermined subsample analyses were conducted. Results: A total of 401 participants were eligible for the study (248 women [62%]; mean [SD] age, 53.5 [10.2] years; mean [SD] body mass index, 34.6 [6.2]). One hundred one patients were randomized to receive α-cyclodextrin plus hydrolyzed ginseng, 99 were randomized to receive α-cyclodextrin plus placebo, 101 were randomized to receive placebo plus hydrolyzed ginseng, and 100 were randomized to receive placebo plus placebo. For 200 participants taking α-cyclodextrin compared with 201 participants taking placebo, there was no difference in total cholesterol after 6 months (-1.5 mg/dL; 95% CI, -6.6 to 3.5 mg/dL; P = .51). For 202 participants taking hydrolyzed ginseng compared with 199 participants taking placebo, there was no difference in fasting plasma glucose after 6 months (0.0 mg/dL; 95% CI, -1.6 to 1.8 mg/dL; P = .95). Use of α-cyclodextrin was associated with constipation (16 participants vs 4 participants; P = .006) and cough (8 participants vs 1 participant; P = .02). Use of hydrolyzed ginseng was associated with rash and pruritus (13 participants vs 2 participants; P = .006). Only 37 of 401 participants (9.2%) experienced these adverse events. Conclusions and Relevance: Although they are safe for use, there was no benefit found for either α-cyclodextrin for cholesterol control or hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001302640.

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet.

BACKGROUND: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. METHODS: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. RESULTS: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. CONCLUSIONS: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

Neutrophil Counts to High-Density Lipoprotein Cholesterol Ratio: a Potential Predictor of Prognosis in Acute Ischemic Stroke Patients After Intravenous Thrombolysis.

Neutrophil counts to high-density lipoprotein cholesterol ratio (NHR) is a relatively new and readily available indicator, and our study aimed to demonstrate its relationship with short-term prognosis after intravenous thrombolysis in acute ischemic stroke (AIS) patients and to make a simple comparison with other prognostic indicators. We compared demographic and laboratory characteristics of AIS patients and healthy controls and grouped AIS patients according to NHR tertiles to contrast 3-month outcomes. Univariate and multivariate regression analyses were carried to further analyze the relationship between NHR and prognosis. Moreover, we compared the accuracy of several factors using receiver-operating characteristic curve. NHR levels of AIS patients were higher than those of healthy controls (p < 0.001). The NHR levels were significantly higher in AIS patients with poor prognosis than those with good prognosis (p = 0.001) and were higher in patients with severe stroke than those with mild stroke (p = 0.011). Multivariate logistic regression analysis indicated that elevated NHR was an independent predictor of poor outcomes (odds ratio = 4.570; 95% CI, 1.841-11.340; p = 0.001). High NHR levels were associated with poor 3-month outcomes after intravenous thrombolysis in AIS patients.

Cumulative non-HDL-cholesterol burden in patients with hypertriglyceridemia receiving long-term fibrate therapy: Real life data from a lipid clinic cohort.

OBJECTIVE: Though epidemiological data suggest that an elevated triglyceride (TG) level may be a risk factor for coronary artery disease (CAD), there is still insufficient clinical evidence. This study was designed to evaluate the real-life efficacy and side effects of fibrate treatment for hypertriglyceridemia seen in a lipid clinic, as well as cardiovascular and diabetic outcomes. METHODS: This retrospective study evaluated patients who were followed-up for a diagnosis of hypertriglyceridemia at the lipid outpatient clinic of the Ege University Cardiology Department between 1997 and 2018. Data of demographic and clinical characteristics were obtained from hospital records. All patients (n=240) with at least 1 year of follow-up were included in the analysis. During follow-up, patients were treated with fenofibrate, and less frequently, gemfibrozile (14 patients), at different doses according to the TG level and disease severity. RESULTS: Of the study population, 23% had CAD, 21% were diabetic, and 52% were obese. On admission, 20% were using fibrates and 17% were on statins. The mean admission lipid levels were TG: 281±194 mg/dL, low-density lipoprotein cholesterol: 115±37 mg/dL, high-density lipoprotein (HDL) cholesterol: 43±13 mg/dL, and non-HDL cholesterol: 166±42 mg/dL. The mean length of follow-up was 5.3±4.7 years (range: 1-16 years). A total of 8 (4.3%) patients had adverse effects during follow-up (1 on statin combination and 7 on fibrates alone). The side effects observed were an elevation of liver enzymes in 3, myalgia in 2, insomnia in 1, malaise in 1, and a skin rash in 1 patient. No rhabdomyolysis or myopathy was seen. During follow-up, diabetes developed in 14 and cardiovascular disease (CVD) in 14 patients. The cumulative non-HDL cholesterol level was significantly high in patients who developed diabetes or CVD. Receiver operating curve analysis indicated that a cumulative non-HDL cholesterol value of 1016 mg/dL was predictive of the development of diabetes mellitus or CVD with 85% sensitivity and 70% specificity. CONCLUSION: In real life, long-term fibrate use is effective and safe. The cumulative non-HDL cholesterol burden can be used to assess the efficacy of treatment as a simple and easily calculated method. Large studies are needed to further clarify the value of this parameter in predicting the development of both diabetes and CVD.

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.

Effects of Statins on Lipid Profile of Kidney Transplant Recipients: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To assess the benefits of statins on lipid profile in kidney transplant recipients via a meta-analysis. METHODS: We systematically identified peer-reviewed clinical trials, review articles, and treatment guidelines from PubMed, Embase, the Cochrane Library, Wanfang, Chinese National Knowledge Infrastructure (CNKI), SinoMed (CBM), and Chongqing VIP databases from inception to April 2019. In the analysis, only randomized controlled clinical trials performed in human were included. RESULTS: Eight articles were included in the analysis, involving 335 kidney transplant recipients who received statins and 350 kidney transplant patients as the control group. Results revealed that statins improved the lipid profile of kidney transplant recipients. Specifically, statin therapy significantly reduced total cholesterol and low-density lipoprotein cholesterol. However, it had no effects on high-density lipoprotein cholesterol and triglyceride levels. CONCLUSIONS: The present study provides valuable knowledge on the potential benefits of statins in kidney transplant recipients. This meta-analysis shows that statin therapy modifies the lipid profile in this patient population.

A Novel Role for CETP as Immunological Gatekeeper: Raising HDL to Cure Sepsis?

Raising HDL using cholesteryl ester transfer protein (CETP) inhibitors failed to show a clinically relevant risk reduction of cardiovascular disease in clinical trials, inviting reconsideration of the role of CETP and HDL in human physiology. Based on solid evidence from studies with isolated macrophages, rodents, and humans, we propose that a major function of CETP may be to modulate HDL in order to help resolve bacterial infections. When gram-negative bacteria invade the blood, as occurs in sepsis, Kupffer cells lose their expression of CETP to increase HDL levels. This rise in HDL prevents systemic endotoxemia by binding lipopolysaccharide and induces a systemic proinflammatory response in macrophages to mediate bacterial clearance. This raises the interesting possibility to repurpose CETP inhibitors for the treatment of sepsis.

Exendin-4 Improves Diabetic Kidney Disease in C57BL/6 Mice Independent of Brown Adipose Tissue Activation.

BACKGROUND: The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM). METHODS: In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate. RESULTS: The expressions of UCP-1, PGC-1α, ATGL, and CD36 in BAT of DM mice were all downregulated, which could be upregulated by exendin-4 treatment with significant effects on ATGL and CD36. BAT-excision exacerbated high blood glucose (BG) with no significant effect on the serum lipid level. Exendin-4 significantly lowered the level of serum triglycerides (TG) and low-density lipoprotein- (LDL-) c, 24 h urine albumin, and 8-OH-dG; improved renal fibrosis and lipid accumulation; and activated renal AMP-activated protein kinase (AMPK) in diabetic mice regardless of BAT excision. In vitro, there was no significant effect of exendin-4 on brown or white adipogenesis. However, exendin-4 could improve lipid accumulation and myofibroblast-like phenotype transition of mesangial cells induced by oleate via activating the AMPK pathway. CONCLUSIONS: Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Recent advances in synthetic pharmacotherapies for dyslipidaemias.

Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). LDL-C is unquestionably causal in the development of atherogenesis and atherosclerotic cardiovascular disease, but new options are required to address triglyceride-rich lipoproteins and lipoprotein(a). For hypercholesterolaemia, pitavastatin provides a very low dose and potent statin that does not adversely affect glucose metabolism; bempedoic acid acts at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and is not associated with muscular side effects. For hypertriglyceridaemia, pemafibrate displays a unique and selective agonist activity on peroxisomal proliferator activated receptor-α that does not elevate homocysteine or creatinine. Although omega-3 fatty acids supplementation is not effective in secondary prevention, high dose eicosapentaenoic ethyl ester can lead to a remarkable fall in first and recurrent events in high risk patients with hypertriglyceridaemia/low HDL-C. Gemcabene, a dicarboxylic acid regulating apolipoprotein B-100, is effective in reducing both cholesterol and triglycerides. Among cholesteryl ester transfer protein antagonists that elevate HDL-C, only anacetrapib reduces cardiovascular events. Probucol stimulates reverse cholesteryl ester transport, lowers LDL-C stabilizing plaques and may lower incidence of cardiovascular events. These agents, which act through novel mechanisms, afford good and potentially safe treatment choices that may increase adherence and the attainment of therapeutic targets.

Corn silk decoction for blood lipid in patients with angina pectoris: A systematic review and meta-analysis.

The aims of this study were to evaluate the efficacy of corn silk decoction on lipid profile in patients with angina pectoris. PubMed, Cochrane, Embase, Google Scholar, Chongqing VIP Chinese Science and Technology Periodical Database, China National Knowledge Infrastructure, and Wanfang database were searched up to January 2019 for randomized controlled trials that assessed the impact of corn silk decoction on total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in patients with angina pectoris. Study evaluation and synthesis methods were in accordance with the Cochrane Handbook, and data were analyzed using Review Manager (version 5.3) software. Random effects model was applied in this systematic review and meta-analysis to compensate for potential heterogeneity among the included studies. A total of four randomized controlled trials were eligible for meta-analysis. Pooled results of these studies indicated that corn silk decoction might improve high-density lipoprotein cholesterol and reduce total cholesterol, triglycerides, and low-density lipoprotein cholesterol in patients with angina pectoris. Subgroup analyses showed that corn silk decoction or modified corn silk decoction plus conventional pharmaceutical treatment could have favorable effects on blood lipids. However, the lack of blinding in most studies may have led to overestimation of these effects. Further studies with better design are needed to confirm these findings.

[The effect of metformin on lipid parameters and on cardiovascular risk in patients with type 2 diabetes without statin therapy]. / A metformin hatása a vérzsírértékekre, illetve a szív és érrendszeri kockázatra sztatinkezelésben nem részesülo 2-es típusú cukorbetegekben.

Introduction: Some meta-analyses suggested a positive effect of metformin therapy on lipid parameters, but the potential beneficial effect of metformin on cardiovascular risk in type 2 diabetes is not entirely clear. Aim: We investigated the effect of metformin therapy on lipid parameters and cardiovascular risk in patients with type 2 diabetes. Method: In a cross-sectional, monocentric study, 102 patients with type 2 diabetes without lipid-lowering medication were analysed for lipid profile and cardiovascular risk (United Kingdom Prospective Diabetes Study Risk Calculator) depending on metformin therapy. The patients were divided into two subgroups regarding with (n = 52) or without metformin therapy (n = 50). Results: Patients with metformin therapy had significantly lower total cholesterol and LDL cholesterol levels than patients without metformin (p<0.01 and p<0.05). This effect was independent from glucose control. No intrinsic effect of metformin could be found on systolic blood pressure, HDL cholesterol, triglycerides, and long-term cardiovascular risk using a multivariable risk assessment score. Conclusion: Metformin therapy has beneficial effects on cholesterol levels without improving cardiovascular risk in patients with type 2 diabetes. Orv Hetil. 2019; 160(34): 1346-1352.

Control lipídico y factores de riesgo asociados, antes del padecimiento del primer evento cardiovascular / Lipid control and associated risk factors, before suffering from the first cardiovascular event

Objetivos: Conocer el grado de control lipídico previo al primer accidente cardiovascular en población atendida durante 2013 en Atención Primaria. Analizar la distribución de dichos eventos según intervalos de control de colesterol LDL (LDL-col), colesterol HDL (HDL-col) y triglicéridos (TG). Método: Estudio descriptivo transversal multicéntrico. Sujetos: mayores de 18 años atendidos en centros del Servicio (SAP) Baix Llobregat Nord, que habían sufrido un primer evento (ECV) isquémico cardiaco (CI) o cerebral (CV) del 01/01/2013 al 31/12/2013. Mediciones: edad, sexo, tabaquismo, hipertensión arterial, diabetes, dislipemia, obesidad, colesterol total (col-tot), LDL-col, HDL-col, TG, presión arterial sistólica, diastólica, IMC, HbA1c, índices aterogénicos, REGICOR, fármacos. Resultados: Trescientos setenta y nueve sujetos afectos, 197 (52%) cardiaco y 182 (48%) cerebral. Doscientos veinticinco (59,4%) varones; edad media en el diagnóstico 68,9 años (DS 13,7), 71,2 (DS 14,4) en CV (p: 0,001). Hipertensión 214 (56,5%), diabetes 113 (29,8%), DLP 193 (50,9%). Casos en LDL < 100-159: 88%, HDL ≥ 40/50: 72,8%, TG < 150: 71,3%. Media col-tot: 198,3 mg/dl (DS 40,2); LDL-col 121 (DS 33,8), LDL-col < 130: 170 (58,6%). Media HDL-col: 52,5 mg/dl (DS 15,4) y TG: 130,9 mg/dl (DS 73,2) (CI: 139,5 [DS 84,2] vs. CV: 120,9 [DS 55,9] [p: 0,003]). col-tot/HDL-col óptimo 67%, TG/HDL-col óptimo 39,8%. CI: col-tot/HDL-col óptimo varón vs. mujer: 51,2 vs. 76,9% (p 0,002); TG/HDL-col óptimo varón vs. mujer: 28% vs. 53,8% (p 0,004). Conclusiones: La cuantía de eventos fue similar en ambos territorios, y la edad media en el diagnóstico algo mayor en CV. Hipertensión, DLP y obesidad son los FRCV más prevalentes, y su control en prevención primaria es susceptible de mejora. La mayor parte de los casos se agruparon en los intervalos lipídicos LDL < 100-159 mg/dl, HDL ≥ 40/50 mg/dl y TG < 150 mg/dl

Objective: To ascertain the degree of lipidic control before the first cardiovascular accident in population attended during 2013 at Primary Care. To analyze the distribution of these events depending on control intervals of cholesterol LDL (LDL-chol), cholesterol HDL (HDL-chol) and triglycerides (TG). Method: A multicentric cross-sectional, descriptive study on above 18-year-old people attended at the centres of the Primari Care Service (PCS) Baix Llobregat Nord, who had suffered a first cardiac or cerebral ischemic attack from 01/01/2013 to 31/12/2013. Variables collected included age,sex, smoking, high blood preassure,diabetes, dyslipidemia (DLP), obesity, total cholesterol (chol-tot), LDL-chol, HDL-chol, TG, systolic and diastolic blood preassure (SBP,DBP), IMC, HbA1c, atherogenic indices, REGICOR, drugs. Results: 379 affected people, among them 197 (52%) heart attack and 182 (48%) stroke (ictus). Two hundred and twenty-five (54.4%) males, diagnosis median age 68.9 years (DS 13.7), 71.2 (DS 14.4) in CV (p: .001). High blood preassure 214 (56.5%), diabetes 113 (29.8%), DLP 193 (50.9%). Cases in LDL< 100-159: 88%, HDL ≥ 40/50: 72.8%, TG < 150: 71.3%. chol-tot average: 198.3 mg/dl (DS 40.2), LDL-chol:121 (DS 33.8), LDL-chol < 130:170 (58.6%). HDL-chol average: 52.5 mg/dl (DS 15.4) and TG: 130.9 mg/dl (DS 73.2) (CI:139.5 [DS 84.2] vs. CV: 120.9 [DS 55.9] [p: .003]). Optimal chol-tot/HDL-chol 67%, optimal TG/HDL-chol 39.8%. CI:optimal chol-tot/HDL-chol male vs. female: 51.2% vs. 76.9% (p: .002); optimal TG/HDL-chol male vs. female: 28% vs. 53.8% (p: .004). Conclusions: The quantity of events was similar in both cardiac and cerebral territories, whereas the median age in the diagnosis was a little higher in CV. High blood preassure, DLP and obesity are the most prevalent FRCV, and its control at primary prevention is improvable. Most of the cases were grouped in the LDL lipid ranges < 100-159 mg/dl, HDL ≥ 40/50 mg/dl and TG < 150 mg/dl