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1.
Comorbidities of HIV infection: role of Nef-induced impairment of cholesterol metabolism and lipid raft functionality.
Sviridov, D, Mukhamedova, N, Makarov, AA, Adzhubei, A, Bukrinsky, M
AIDS (London, England). 2020;(1):1-13
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Abstract
: Combination antiretroviral therapy has dramatically changed the outcome of HIV infection, turning it from a death sentence to a manageable chronic disease. However, comorbidities accompanying HIV infection, such as metabolic and cardio-vascular diseases, as well as cognitive impairment, persist despite successful virus control by combination antiretroviral therapy and pose considerable challenges to clinical management of people living with HIV. These comorbidities involve a number of pathological processes affecting a variety of different tissues and cells, making it challenging to identify a common cause(s) that would link these different diseases to HIV infection. In this article, we will present evidence that impairment of cellular cholesterol metabolism may be a common factor driving pathogenesis of HIV-associated comorbidities. Potential implications for therapeutic approaches are discussed.
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G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases.
DeLeon, C, Wang, DQ, Arnatt, CK
Frontiers in endocrinology. 2020;:578536
Abstract
There are gender differences between men and women in many physiological functions and diseases, which indicates that female sex hormones may be important. Traditionally, estrogen exerts its biological activities by activating two classical nuclear estrogen receptors, ESR1 and ESR2. However, the roles of estrogen in the regulation of physiological functions and the pathogenesis of diseases become more complicated with the identification of the G protein-coupled estrogen receptor (GPER1). Although many GPER1-specific ligands have been developed, the therapeutic mechanisms of exclusively targeting GPER1 are not yet well understood. Translational applications and clinical trial efforts for the identified GPER1 ligands have been focused primarily on the reproductive, cardiovascular, nervous, endocrine, and immune systems. More recently, research found that GPER1 may play an important role in regulating the digestive system. Cholesterol gallstone disease, a major biliary disease, has a higher prevalence in women than in men worldwide. Emerging evidence implies that GPER1 could play an important role, independent of the classical ESR1, in the pathophysiology of cholesterol gallstones in women. This review discusses the complex signaling pathways of three estrogen receptors, highlights the development of GPER1-specific ligands, and summarizes the latest advances in the role of GPER1 in the pathogenesis of gallstone formation.
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The Effect of Three Mediterranean Diets on Remnant Cholesterol and Non-Alcoholic Fatty Liver Disease: A Secondary Analysis.
Campanella, A, Iacovazzi, PA, Misciagna, G, Bonfiglio, C, Mirizzi, A, Franco, I, Bianco, A, Sorino, P, Caruso, MG, Cisternino, AM, et al
Nutrients. 2020;(6)
Abstract
BACKGROUND Elevated fasting remnant cholesterol (REM-C) levels have been associated with an increased cardiovascular risk in patients with metabolic syndrome (Mets) and Non-Alcoholic Fatty Liver Disease (NAFLD). We aimed to estimate the effect of different diets on REM-C levels in patients with MetS, as well as the association between NAFLD and REM-C. METHODS This is a secondary analysis of the MEDIDIET study, a parallel-arm Randomized Clinical Trial (RCT). We examined 237 people with MetS who underwent Liver Ultrasound (LUS) to assess the NAFLD score at baseline, 3-, and 6-months follow-up. Subjects were randomly assigned to the Mediterranean diet (MD), Low Glycemic Index diet (LGID), or Low Glycemic Index Mediterranean diet (LGIMD). REM-C was calculated as [total cholesterol-low density lipoprotein cholesterol (LDL-C)-high density lipoprotein cholesterol (HDL-C)]. RESULTS REM-C levels were higher in subjects with moderate or severe NAFLD than in mild or absent ones. All diets had a direct effect in lowering the levels of REM-C after 3 and 6 months of intervention. In adherents subjects, this effect was stronger among LGIMD as compared to the control group. There was also a significant increase in REM-C levels among Severe NAFLD subjects at 3 months and a decrease at 6 months. CONCLUSIONS fasting REM-C level is independently associated with the grade of severity of NAFLD. LGIMD adherence directly reduced the fasting REM-C in patients with MetS.
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Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer.
Criscuolo, D, Avolio, R, Calice, G, Laezza, C, Paladino, S, Navarra, G, Maddalena, F, Crispo, F, Pagano, C, Bifulco, M, et al
Cells. 2020;(4)
Abstract
Despite initial chemotherapy response, ovarian cancer is the deadliest gynecologic cancer, due to frequent relapse and onset of drug resistance. To date, there is no affordable diagnostic/prognostic biomarker for early detection of the disease. However, it has been recently shown that high grade serous ovarian cancers show peculiar oxidative metabolism, which is in turn responsible for inflammatory response and drug resistance. The molecular chaperone TRAP1 plays pivotal roles in such metabolic adaptations, due to the involvement in the regulation of mitochondrial respiration. Here, we show that platinum-resistant ovarian cancer cells also show reduced cholesterol biosynthesis, and mostly rely on the uptake of exogenous cholesterol for their needs. Expression of FDPS and OSC, enzymes involved in cholesterol synthesis, are decreased both in drug-resistant cells and upon TRAP1 silencing, whereas the expression of LDL receptor, the main mediator of extracellular cholesterol uptake, is increased. Strikingly, treatment with statins to inhibit cholesterol synthesis reduces cisplatin-induced apoptosis, whereas silencing of LIPG, an enzyme involved in lipid metabolism, or withdrawal of lipids from the culture medium, increases sensitivity to the drug. These results suggest caveats for the use of statins in ovarian cancer patients and highlights the importance of lipid metabolism in ovarian cancer treatment.
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Effect of dietary intervention with a legume-based food product on malondialdehyde levels, HOMA index, and lipid profile.
Ruiz Esparza Cisneros, J, Vasconcelos-Ulloa, JJ, González-Mendoza, D, Beltrán-González, G, Díaz-Molina, R
Endocrinologia, diabetes y nutricion. 2020;(4):235-244
Abstract
INTRODUCTION Prevalence of overweight and obesity, a condition that promotes development of chronic degenerative diseases, has increased in Mexico in recent years. Implementation of strategies to increase daily consumption of vegetables, legumes, whole grain cereals, and fruits by the population will result in an adequate intake of soluble fiber, antioxidants, protein of vegetable origin, and vitamins. OBJECTIVE To assess the effect of a commercial food product prepared using 6 legumes on some anthropometric and biochemical parameters in apparently healthy subjects. METHODS A randomized dietary intervention trial where subjects in the study group received for three months 15g of the product, administered daily in periods of five days with two days of rest. Before and after intervention, anthropometric and dietary assessments were performed, and serum glucose, lipid profile, insulin, ultrasensitive C-reactive protein, malondialdehyde (MDA) and insulin resistance (HOMA index) were measured. A Mann-Whitney U test was used and values of P<0.05 were considered statistically significant. RESULTS Sixty university students were included in the study (53% males). At the end of the intervention, decreases were seen in serum glucose levels (P=0.001), MDA (P=0.001) and HOMA index (P=0.017), but there were no significant changes in all other parameters. CONCLUSIONS Daily intake of 15g of the legume-based food product improved serum glucose and malondialdehyde levels in the study group, as well as insulin resistance; which could be attributed to the presence of polyphenols and isoflavones such as genistein in legumes.
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Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol.
Georgakis, MK, Malik, R, Anderson, CD, Parhofer, KG, Hopewell, JC, Dichgans, M
Brain : a journal of neurology. 2020;(2):597-610
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Abstract
Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.
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The Effects of Different Degrees of Carbohydrate Restriction and Carbohydrate Replacement on Cardiometabolic Risk Markers in Humans-A Systematic Review and Meta-Analysis.
Fechner, E, Smeets, ETHC, Schrauwen, P, Mensink, RP
Nutrients. 2020;(4)
Abstract
Low-carbohydrate diets (LCDs) often differ in their diet composition, which may lead to conflicting results between randomized controlled trials. Therefore, we aimed to compare the effects of different degrees of carbohydrate (CHO) restriction on cardiometabolic risk markers in humans. The experimental LCDs of 37 human trials were classified as (1) moderate-low CHO diets (<45-40 E%, n = 13), (2) low CHO diets (<40-30 E%, n = 16), and (3) very-low CHO diets (<30-3 E%; n = 8). Summary estimates of weighted mean differences (WMDs) in selected risk markers were calculated using random-effect meta-analyses. Differences between the LCD groups were assessed with univariate meta-regression analyses. Overall, the LCDs resulted in significant weight loss, reduced diastolic blood pressure BP, and increased total cholesterol and high-density lipoprotein cholesterol (HDL-C), without significant differences between the three LCD groups. Higher low-density lipoprotein cholesterol (LDL-C) concentrations were found with the very-low CHO diets compared to the moderate-low CHO diets. Decreases in triacylglycerol (TAG) concentrations were more pronounced with the low and very-low CHO diets, compared to the moderate-low CHO diets. Substitution of CHO by mainly saturated fatty acids (SFAs) increased total cholesterol, LDL-C, and HDL-C concentrations. Except for LDL-C and TAGs, effects were not related to the degree of CHO restriction. Potential effects of nutrient exchanges should be considered when following LCDs.
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APLP2 gene polymorphisms are associated with high TC and LDL-C levels in Chinese population in Xinjiang, China.
Abuzhalihan, J, Adi, D, Wang, YT, Li, Y, Yang, YN, Ma, X, Li, XM, Xie, X, Liu, F, Chen, BD, et al
Bioscience reports. 2020;(8)
Abstract
Hyperlipidemia is one of the main risk factors for coronary artery disease (CAD). In the present study, we aimed to explore whether the single-nucleotide polymorphisms (SNPs) in amyloid precursor-like protein (APLP) 2 (APLP2) gene were associated with high lipid levels in Chinese population in Xinjiang, China. We recruited 1738 subjects (1187 men, 551 women) from the First Affiliated Hospital of Xinjiang Medical University, and genotyped three SNPs (rs2054247, rs3740881 and rs747180) of APLP2 gene in all subjects by using the improved multiplex ligation detection reaction (iMLDR) method. Our study revealed that the rs2054247 SNP was associated with serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) levels, and high-density lipoprotein cholesterol (HDL-C) in additive model (all P<0.05). The rs747180 SNP was associated with serum TC and LDL-C levels in additive model (all P<0.05). Our study revealed that both rs2054247 and rs747180 SNPs of the APLP2 gene were associated with high TC and LDL-C levels in Chinese subjects in Xinjiang.
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Properties of Lipid Models of Lung Surfactant Containing Cholesterol and Oxidized Lipids: A Mixed Experimental and Computational Study.
Olżyńska, A, Delcroix, P, Dolejšová, T, Krzaczek, K, Korchowiec, B, Czogalla, A, Cwiklik, L
Langmuir : the ACS journal of surfaces and colloids. 2020;(4):1023-1033
Abstract
We introduce and study a multicomponent lipid film mimicking lipid composition of the human lung surfactant. It consists of phospholipids with various lipid headgroups and tail saturation. Furthermore, it includes cholesterol and oxidized lipids. Langmuir trough and fluorescence microscopy experiments are combined with fully atomistic molecular dynamics simulations. The considered lipid mixtures form complex interfacial films with properties modulated by lateral compression. Cholesterol laterally condenses, and oxidized lipids laterally expand the films; both types of molecules increase film miscibility. Oxidized lipids also alter the lipid-water interface enhancing film hydration; this effect can be partially reversed by cholesterol. Regarding presentation of different chemical moieties toward the aqueous subphase, the zwitterionic phosphatidylcholine groups dominate at the lipid-water interface, while both the negatively charged phosphatidylglycerol and hydroxyl group of cholesterol are less exposed. The investigated synthetic lipid-only mimic of the lung surfactant may serve as a basis for further studies involving nonlipid pulmonary surfactant components.
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In vitro analysis of gallstone formation in the presence of bacteria.
Sharma, R, Sachan, SG, Sharma, SR
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2020;(5):473-480
Abstract
AIM: In our previous study, we have isolated different genera of bacteria from gallstones and this intrigued us to study their role in gallstone formation. The isolates exhibited certain biliary activities like urease activity, slime production, and β-glucuronidase production. We aimed to investigate the role of these factors in the formation of gallstone in in vitro conditions at a supersaturated concentration of cholesterol. METHODOLOGY To mimic bile in in vitro state, Brilliant Green Bile Broth (BGBB) media having a composition similar to human bile was used. Four different experimental sets were prepared, each having nine flasks with varying concentrations of cholesterol and CaCO3 (calcium carbonate). Test sets I, II, III, and IV were inoculated with Salmonella, Enterococcus, Helicobacter, and Neisseria respectively, which were isolated from gallstone itself. Out of these four bacteria, only Helicobacter did not possess slime activity. A control set was also established which was devoid of bacteria. The control also had nine flasks with different concentrations of cholesterol and CaCO3. All the sets were incubated in the incubator shaker at 37 °C and 80 revolution per minutes (RPM) for 20 days. RESULT It was observed that the sets having bacteria had a less nucleation time as compared to the control (F = 5.274; p < 0.001). Solidification of gallstone was observed only in the set with bacteria having slime activity (sets I, II, and IV). CONCLUSION The slime activity of bacteria leads to solidification of gallstones, whereas the other activities accelerate the nucleation of gallstone formation enhancing the severity of the disease.