Treatment with β-sitosterol ameliorates the effects of cerebral ischemia/reperfusion injury by suppressing cholesterol overload, endoplasmic reticulum stress, and apoptosis

β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

Hepatic steatosis is associated with dysregulated cholesterol metabolism and altered protein acetylation dynamics in chickens

Background Hepatic steatosis is a prevalent manifestation of fatty liver, that has detrimental effect on the health and productivity of laying hens, resulting in economic losses to the poultry industry. Here, we aimed to systematically investigate the genetic regulatory mechanisms of hepatic steatosis in laying hens.Methods Ninety individuals with the most prominent characteristics were selected from 686 laying hens according to the accumulation of lipid droplets in the liver, and were graded into three groups, including the control, mild hepatic steatosis and severe hepatic steatosis groups. A combination of transcriptome, proteome, acetylome and lipidome analyses, along with bioinformatics analysis were used to screen the key biological processes, modifications and lipids associated with hepatic steatosis.Results The rationality of the hepatic steatosis grouping was verified through liver biochemical assays and RNA-seq. Hepatic steatosis was characterized by increased lipid deposition and multiple metabolic abnormalities. Integration of proteome and acetylome revealed that differentially expressed proteins(DEPs) interacted with differentially acetylated proteins(DAPs) and were involved in maintaining the metabolic balance in the liver. Acetylation alterations mainly occurred in the progression from mild to severe hepatic steatosis, i.e., the enzymes in the fatty acid oxidation and bile acid synthesis pathways were significantly less acetylated in severe hepatic steatosis group than that in mild group(P < 0.05). Lipidomics detected a variety of sphingolipids(SPs) and glycerophospholipids(GPs) were negatively correlated with hepatic steatosis(r ≤-0.5, P < 0.05). Furthermore, the severity of hepatic steatosis was associated with a decrease in cholesterol and bile acid synthesis and an increase in exogenous cholesterol transport.Conclusions In addition to acquiring a global and thorough picture of hepatic steatosis in laying hens, we were able to reveal the role of acetylation in hepatic steatosis and depict the changes in hepatic cholesterol metabolism. The findings provides a wealth of information to facilitate a deeper understanding of the pathophysiology of fatty liver and contributes to the development of therapeutic strategies.

Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage

Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.

Biochemistry and transcriptome analysis reveal condensed tannins alleviate liver injury induced by regulating cholesterol metabolism pathway

Free cholesterol has been considered to be a critical risk factor of nonalcoholic fatty liver disease(NAFLD).It remains unknown whether dietary intake of condensed tannins(CTs)have distinguishable effects to alleviate liver damage caused by a high cholesterol diet.Male C57BL/6 mice were fed a high cholesterol diet for 6 weeks,and given CTs treatment at a dosage of 200 mg/(kg·day)at the same time.The results indicated that compared with mice fed a normal diet,a high cholesterol diet group resulted in significant weight loss,dysregulation of lipid metabolism in blood and liver,and oxidative stress in the liver,but CTs treatment dramatically reversed these negative effects.Hematoxylin and eosin(H&E)staining and frozen section observation manifested that CTs treatment could effectively reduce the deposition of liver cholesterol and tissue necrosis caused by high cholesterol intake.CTs alleviated liver injury mainly by regulating the expression of related genes in cholesterol metabolism pathway and AMPK phosphorylation.Our results confirmed that CTs have remarkable cholesterol lowering and anti-liver injury effects in vivo.

Inhibitory effect of procyanidin B2 and tannin acid on cholesterol esterase and their synergistic effect with orlistat

This study was aimed to analyze the effect of procyanidin B2(PC)and tannin acid(TA)on the activities of cholesterol esterase(CEase)and the inhibitory mechanisms of enzymatic activity.The interaction mechanisms were investigated by enzymatic kinetics,multi-spectroscopy methods,thermodynamics analysis,molecular docking,and dynamic simulations.PC and TA could bind with CEase and inhibit the activity of enzyme in a mixed-competitive manner and non-competitive manner,which was verified by molecular docking simulations and dynamics simulations.Also,PC and TA showed the synergistic inhibition with orlistat.Fluorescence,UVvis and the thermodynamic analysis revealed that the complexes were formed from CEase and inhibitors by noncovalent interaction.As revealed by the circular dichroism results,both PC and TA decreased enzymatic activities by altering the conformations of CEase.The inhibition of PC and TA on CEase might be one mechanism for its cholesterol-lowering effect.

The role of cholesterol metabolism in lung cancer

Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer.Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells.Inhibiting tumor cell cholesterol uptake or biosynthesis pathways,through the modulation of receptors and enzymes such as liver X receptor and sterolregulatory element binding protein 2,effectively restrains lung tumor growth.Similarly,promoting cholesterol excretion yields comparable effects.Cholesterol metabolites,including oxysterols and isoprenoids,play a crucial role in regulating cholesterol metabolism within tumor cells,consequently impacting cancer progression.In lung cancer patients,both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth,proliferation,and metastasis.The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells,B cells,macrophages,myeloid-derived suppressor cells,among others.Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments.Statins,targeting the cholesterol biosynthesis pathway,are widely employed in lung cancer treatment,either as standalone agents or in combination with other drugs.Additionally,drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer.In this review,we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

Associations between remnant cholesterol levels and mortality in patients with diabetes

BACKGROUND Dyslipidemia is frequently present in patients with diabetes.The associations of remnant cholesterol and mortality remains unclear in patients with diabetes.AIM To explore the associations of remnant cholesterol with all-cause and cardiovas-cular mortality in patients with diabetes.METHODS This prospective cohort study included 4740 patients with diabetes who par-ticipated in the National Health and Nutrition Examination Survey from 1999 through 2018.Remnant cholesterol was used as the exposure variable,and all-cause and cardiovascular mortality were considered outcome events.Outcome data were obtained from the National Death Index,and all participants were followed from the interview date until death or December 31,2019.Multivariate proportional Cox regression models were used to explore the associations between exposure and outcomes,in which remnant cholesterol was modeled as both a categorical and a continuous variable.Restricted cubic splines(RCSs)were calculated to assess the nonlinearity of associations.Subgroup(stratified by sex,age,body mass index,and duration of diabetes)and a series of sensitivity analyses were performed to evaluate the robustness of the associations.RESULTS During a median follow-up duration of 83 months,1370 all-cause deaths and 389 cardiovascular deaths were documented.Patients with remnant cholesterol levels in the third quartile had a reduced risk of all-cause mortality[hazard ratio(HR)95%confidence interval(CI):0.66(0.52-0.85)];however,when remnant cholesterol was modeled as a continuous variable,it was associated with increased risks of all-cause[HR(95%CI):1.12(1.02-1.21)per SD]and cardiovascular[HR(95%CI):1.16(1.01-1.32),per SD]mortality.The RCS demonstrated nonlinear associations of remnant cholesterol with all-cause and cardiovascular mortality.Subgroup and sensitivity analyses did not reveal significant differences from the above results.CONCLUSION In patients with diabetes,higher remnant cholesterol was associated with increased risks of all-cause and cardiovascular mortality,and diabetes patients with slightly higher remnant cholesterol(0.68-1.04 mmol/L)had a lower risk of all-cause mortality.

Causal associations between intermediate very-low-density lipoprotein cholesterol-to-total lipids ratio and peptic ulcer:A bidirectional Mendelian randomization study

BACKGROUND Previous epidemiologic investigations have consistently demonstrated a strong association between the ratio of cholesterol to total lipids in medium very-lowdensity lipoprotein(VLDL)and the occurrence of peptic ulcers(PU).However,the precise causal relationship between these factors remains ambiguous.Consequently,this study aims to elucidate the potential correlation between the ratio of cholesterol to total lipids in medium VLDL and the incidence of peptic ulcer.AIM To investigate the ratio of cholesterol to total lipids in medium very-low-density lipoprotein(VLDL)association with PU via genetic methods,guiding future clinical research.METHODS Genome-wide association study(GWAS)datasets for the ratio of cholesterol to total lipids in intermediate VLDL and peptic ulcer were retrieved from the IEU OpenGWAS project(https://gwas.mrcieu.ac.uk).For the forward Mendelian randomization(MR)analysis,72 single nucleotide polymorphisms(SNPs)were identified as instrumental variables.These SNPs were selected based on their association with the ratio of cholesterol to total lipids in intermediate VLDL,with peptic ulcer as the outcome variable.Conversely,for the inverse MR analysis,no SNPs were identified with peptic ulcer as the exposure variable and the ratio of cholesterol to total lipids in intermediate VLDL as the outcome.All MR analyses utilized inverse variance weighted(IVW)as the primary analytical method.Additionally,weighted median and MR-Egger methods were employed as supplementary analytical approaches to assess causal effects.Egger regression was used as a supplementary method to evaluate potential directional pleiotropy.Heterogeneity and multiplicity tests were conducted using the leave-one-out method to evaluate result stability and mitigate biases associated with multiple testing.RESULTS The genetically predicted ratio of cholesterol to total lipids in medium VLDL was significantly associated with an elevated risk of peptic ulcer(IVW:OR=2.557,95%CI=1.274-5.132,P=0.008).However,no causal association of peptic ulcer with the ratio of cholesterol to total lipids in medium VLDL was observed in the inverse Mendelian randomization analysis.CONCLUSION In conclusion,our study reveals a significant association between the ratio of cholesterol to total lipids in medium VLDL and an elevated risk of peptic ulcers.However,further validation through laboratory investigations and larger-scale studies is warranted to strengthen the evidence and confirm the causal relationship between these factors.

Cholesterol and Sericin as First Aid for Damaged Cells

Cells are surrounded by a double-layered phospholipid cell membrane responsible for the isolation of intracellular contents, active regulation of uptake from the extracellular environment, and intercellular connection and communication. These cell membranes must be intact and functionally active for cell survival and biological functioning. Compromised damage repair mechanisms usually result in impaired cellular homeostasis, leading to early or late problems. Chronic myopathies, certain myocardial diseases, aging, and acute or chronic neurodegenerative diseases (like Parkinson and Alzheimer) are directly related to cell membrane damage. This study examined the effect of a cholesterol-loaded nanoparticle (methyl-beta cyclodextrin) or the silk protein sericin on cell membrane and DNA integrity and cell viability in an in vitro cell damage model (frozen-thawed rabbit sperm cells). The cells were stored in liquid nitrogen (-196°C), thawed in small batches, and treated with cholesterol-loaded cyclodextrin or sericin before incubation at 35°C for 4 hours. Cell membrane integrity, DNA damage, and viability rates were assessed immediately after thawing and after the incubation period. The administration of sericin and cholesterol in a cell damage model increased cell survival and reduced DNA damage over a 4-hour post-thaw incubation period, suggesting their potential use as a “first aid” intervention at the cellular level.

Association between sensitivity to thyroid hormones and non-highdensity lipoprotein cholesterol levels in patients with type 2 diabetes mellitus

BACKGROUND Dyslipidemia and type 2 diabetes mellitus(T2DM)are chronic conditions with substantial public health implications.Effective management of lipid metabolism in patients with T2DM is critical.However,there has been insufficient attention given to the relationship between thyroid hormone sensitivity and dyslipidemia in the T2DM population,particularly concerning non-high-density lipoprotein cholesterol(non-HDL-C).AIM To clarify the association between thyroid hormone sensitivity and dyslipidemia in patients with T2DM.METHODS In this cross-sectional study,thyroid hormone sensitivity indices,the thyroid feedback quantile-based index(TFQI),the thyroid-stimulating hormone index(TSHI),the thyrotrophic T4 resistance index(TT4RI),and the free triiodothyronine(FT3)/free thyroxine(FT4)ratio were calculated.Logistic regression analysis was performed to determine the associations between those composite indices and non-HDL-C levels.Random forest variable importance and Shapley Additive Explanations(SHAP)summary plots were used to identify the strength and direction of the association between hyper-non-HDL-C and its major predictor.RESULTS Among the 994 participants,389(39.13%)had high non-HDL-C levels.Logistic regression analysis revealed that the risk of hyper-non-HDL-C was positively correlated with the TFQI(OR:1.584;95%CI:1.088-2.304;P=0.016),TSHI(OR:1.238;95%CI:1.034-1.482;P=0.02),and TT4RI(OR:1.075;95%CI:1.006-1.149;P=0.032)but was not significantly correlated with the FT3/FT4 ratio.The relationships between composite indices of the thyroid system and non-HDL-C levels differed according to sex.An increased risk of hyper-non-HDL-C was associated with elevated TSHI levels in men(OR:1.331;95%CI:1.003-1.766;P=0.048)but elevated TFQI levels in women(OR:2.337;95%CI:1.4-3.901;P=0.001).Among the analyzed variables,the average SHAP values were highest for TSHI,followed by TT4RI.CONCLUSION Impaired sensitivity to thyroid hormones was associated with high non-HDL-C levels in patients with T2DM.

Correlation of Helicobacter pylori infection with high-density lipoprotein cholesterol levels and pulse wave conduction velocity

Background:Helicobacter pylori(HP)is associated with several gastrointestinal diseases,including peptic ulcer diseases and gastric cancer,and non-gastrointestinal diseases such as hypertension and Alzheimer's disease.However,the relationship between HP and lipid metabolism and atherosclerosis remains unclear.This study aims to investigate the association between H.pylori infection and high-density lipoprotein cholesterol levels and pulse wave conduction velocity.Methods:This is a report of a cross-sectional study that collected data from 2,827 participants.The data collected included results of life questionnaires,laboratory tests,13C-urea breath test(13C-UBT),and pulse wave conduction velocity test.Based on the results of the 13C-UBT test,the subjects were divided into two groups:the HP-uninfected group(HP−)and the HP-infected group(HP+).The study compared the differences in HDL-C levels and brachial-ankle pulse wave velocity(baPWV)between the two groups.One-way regression analysis was used to identify potential factors affecting HDL-C levels in the study population.Multiple regression equations were presented to analyze whether HP infection was an independent risk factor for abnormal HDL-C metabolism in the population.Results:Univariate analysis demonstrated that high-density lipoprotein cholesterol(HDL-C)levels were significantly lower in the HP+group compared to the HP−group,with a mean difference ofβ=−18.1 mg/dl(95%CI:−19.3 to−17.0,P<0.001).After adjusting for all variables,the HDL-C levels remained lower in the HP+group compared to the HP-group,with a mean difference ofβ=−17.4 mg/dl(95%CI:−18.2 to−16.7,P<0.001).These findings suggest that H.pylori infection is independently associated with abnormal HDL-C metabolism.Additionally,brachial-ankle pulse wave velocity(baPWV)was higher in the HP+group than in the HP−group on both sides.On the right side,the baPWV was 1,713.4±231.4 cm/s in the HP+group compared to 1,542.8±237.5 cm/s in the HP−group(t=−18.30,P<0.001).On the left side,the baPWV was 1,743.7±238.8 cm/s in the HP+group compared to 1,562.8±256.3 cm/s in the HP−group(t=−18.23,P<0.001).These results indicate a significant association between H.pylori infection and increased arterial stiffness,as measured by baPWV.Conclusion:Helicobacter pylori infection is associated with a decrease in high-density lipoprotein cholesterol levels and an increase in pulse wave conduction velocity.

Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury

Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.

The Great Cholesterol Quandary and Global Consciousness Awakening

Ancestors of human species have been living on the planet earth for about six million years while the modern form of humans only evolved about 200,000 years ago. Civilization is only about 6000 years old, and industrialization started in the 1800s. World population interconnectedness is enhanced with love and mercy but disrupted with dishonest, lies and wars. Human species has been feeding on animal fat as the finest and prime source of energy for all human history. In 1953 Ancel Keys and collaborates illusionized human kind that their historical source of energy is toxic. Massive health, behavioral as well as economic consequences followed. Human hearts known historically to be the seat of spirit, soul and emotions is proven by our group to orchestrate with global energetic fields. Global consciousness as represented by the planetary electromagnetic fields is in critical need to be feed with awakening merciful information. Documents refuting Ancek Keys dogma and reverting humanity to the truth in their energy source is presented in this review. The harmony we expect is not only physiological but will affect our global planetary environment for the wellbeing of human species in earth.

The role of cholesterol in modifying the lipid-lowering effects of Fuzhuan brick-tea in Caenorhabditis elegans via SBP-1/SREBP

Fuzhuan brick-tea(FZT)has long been consumed for its supposed weight loss and lipid-lowering benefi ts.In this study,we show that the regulation of fat storage in Caenorhabditis elegans from a water extract of FZT was affected by cholesterol levels.We found that FZT signifi cantly decreased fat storage under normal cholesterol levels or in a cholesterol-free diet,while lipid accumulation was increased for a high cholesterol diet.Moreover,this mechanism may involve the conserved sterol regulatory element-binding protein(SREBP)/mediator-15(MDT-15)signaling pathway and the nuclear hormone receptor NHR-80.In addition,lipid synthesis-related genes inhibited by FZT were partially affected by a cholesterol-free diet.Thus,our fi ndings suggested that the potential lipid-lowering effects of FZT may depend on the cholesterol level,which may help to improve the consumption of FZT.

Chronic Supplementation with L-Isoleucine Alone or in Combination with Exercise Reduces Hepatic Cholesterol Levels with No Effect on Serum Glucose, Insulin, or Lipids in Rats Fed a High Fructose Diet

The thought of using branched-chain amino acids (BCAA) in the prevention and treatment of certain disorders is becoming increasingly popular. Individual BCAA use has been associated with improving glucose tolerance and liver disease. Previous studies have cited improvements in glucose metabolism with a single dose of L-isoleucine (ILE). However, it is still unclear whether chronic consumption of ILE has any direct benefit. The objective of this study was to examine the influence of chronic ILE supplementation alone or in combination with exercise on fasting serum glucose, insulin, lipids, and lipoprotein cholesterol levels;glucose tolerance;and hepatic lipids in rats. Male Sprague-Dawley rats (n = 40) were divided into Control (low fructose diet);High Fructose diet (HF);HF plus 1.5% ILE (HF + ILE);HF plus exercise (HF + EX);and HF plus 1.5% ILE and exercise (HF + ILE + EX). The HF diets consisted of 70% kcalories from fructose. After 6 weeks of treatment, no significant differences were observed between groups for changes in fasting serum glucose, insulin, lipids, or lipoprotein cholesterol levels. However, hepatic total cholesterol was significantly lower in the HF + ILE + EX compared to the Control and HF, while, the HF + ILE had significantly lower hepatic free cholesterol compared to the HF. We also found no differences between groups for serum glucose response following an oral glucose tolerance test. In conclusion, our study shows that ILE supplementation in rats does not influence serum glucose and lipid biomarkers but may have an influence on lipid metabolic pathways within the liver.

Lower Baseline LDL Cholesterol Affects All-cause Mortality in Patients with First Percutaneous Coronary Intervention

Objective Foreign studies have reported that coronary artery disease(CAD) patients with high baseline low-density lipoprotein cholesterol(LDL-C) may have a good prognosis, which is called the “cholesterol paradox”. This study aimed to examine whether the “cholesterol paradox” also exists in the Chinese population.Methods A total of 2,056 patients who underwent the first percutaneous coronary intervention(PCI)between 2014 and 2016 were enrolled in this retrospective cohort study and classified into two groups based on baseline LDL-C = 2.6 mmol/L(100 mg/d L). The outcomes of interest included major adverse cardiovascular events(MACE), all-cause mortality, recurrent nonfatal myocardial infarction, unexpected coronary revascularization, or any nonfatal stroke.Results All-cause mortality occurred in 8 patients(0.7%) from the low-LDL-C group and 12 patients(2.4%) in the high-LDL-C group, with a significant difference between the two groups(adjusted hazard ratio: 4.030, 95% confidence interval: 1.088–14.934;P = 0.037). However, no significant differences existed for the risk of MACE or other secondary endpoints, such as unexpected revascularization, nor any nonfatal stroke in the two groups.Conclusion In this study, a high baseline LDL-C was not associated with a low risk of clinical outcomes in CAD patients undergoing first PCI, which suggested that the “cholesterol paradox” may be inapplicable to Chinese populations.

Sodium butyrate alleviates deoxynivalenol-induced hepatic cholesterol metabolic dysfunction via RORγ-mediated histone acetylation modification in weaning piglets

Background:Cholesterol is an essential component of lipid rafts in cell plasma membrane,which exerts a hepatoprotective role against mycotoxin exposure in pigs,and cholesterol metabolism is vulnerable to epigenetic histone acetylation.Therefore,our present study aimed to investigate whether a histone deacetylase inhibitor(sodium butyrate [NaBu]) could protect the porcine liver from deoxynivalenol(DON) exposure by modulating cholesterol metabolism.Herein,we randomly divided 28 pigs into four groups,which were fed an uncontaminated basal diet,contaminated diet(4 mg DON/kg),uncontaminated diet supplemented with 0.2% NaBu or 4 mg/kg DON contaminated diet(4 mg DON/kg) supplemented with 0.2% NaBu for 28 d.Results:We found that the serum alanine transaminase(ALT),aspartate transaminase(AST),and alkaline phosphatase(ALP) were all increased in pigs exposed to DON,indicative of significant liver injury.Furthermore,the cholesterol content in the serum of DON-exposed pigs was significantly reduced,compared to the healthy Vehicle group.Transcriptome analysis of porcine liver tissues revealed that the cholesterol homeostasis pathway was highly enriched due to DON exposure.In which we validated by qRT-PCR and western blotting that the cholesterol program was markedly activated.Importantly,NaBu effectively restored parameters associated with liver injury,along with the cholesterol content and the expression of key genes involved in the cholesterol biosynthesis pathway.Mechanistically,we performed a ChIP-seq analysis of H3K27ac and showed that NaBu strongly diminished DON-increased H3K27ac genome-wide enrichment.We further validated that the elevated H3K27ac and H3K9ac occupancies on cholesterol biosynthesis genes were both decreased by NaBu,as determined by ChIP-qPCR analysis.Notably,nuclear receptor RORγ,a novel regulator of cholesterol biosynthesis,was found in the hyperacetylated regions.Again,a remarkable increase of RORγ at both mRNA and protein levels in DON-exposed porcine livers was drastically reduced by NaBu.Consistent with RORγ expression,NaBu also hindered RORγ transcriptional binding enrichments on these activated cholesterol biosynthesis genes like HMGCR,SQLE,and DHCR24.Furthermore,we conducted an in vitro luciferase reporter assay to verify that porcine RORγ directly bonds to the promoters of the above target genes.Conclusions:Collectively,our results demonstrate the utility of the natural product Na Bu as a potential anti-mycotoxin nutritional strategy for regulating cholesterol metabolism via RORγ-mediated histone acetylation modification.

Similarity of Binding Potentials Between Plant DUF538 and Animal Lipocalin: Cholesterol Binding Ability of DUF538

Objective DUF538(domain of unknown function 538) domain containing proteins are known as putative hypothetical proteins in plants. Until yet, there is no much information regarding their structure and function. Methods In the present research work, the homologous structures and binding potentials were identified between plant/mammalian lipocalins and plant DUF538 protein by using bioinformatics and experimental tools including molecular dynamics simulation, molecular docking and recombinant technology-based techniques. Results Molecular docking analysis of their interactions with lipidic ligands including cholesterol and palmitic acid revealed the similar and comparable binding potentials between DUF538 and lipocalin proteins. Both the test proteins were found to have more affinity to cholesterol molecule in compare to palmitic acid. By using recombinant technology-based experiments, the heterologously expressed and purified fused product of DUF538 protein exhibited about 61% cholesterol binding ability. Conclusion As a conclusion, plants DUF538 protein family was predicted to be the structural and may be the functional homologues of plants/animals lipocalin superfamily.

Cholesterol paradox in the community-living old adults:is higher better?

OBJECTIVE To evaluate the associations of lipid indicators and mortality in Beijing Elderly Comprehensive Health Cohort Study.METHODS A prospective cohort was conducted based on Beijing Elderly Comprehensive Health Cohort Study with 4499 com-munity older adults.After the baseline survey,the last follow-up was March 31,2021 with an average 8.13 years of follow-up.Cox proportional hazard model was used to estimate the hazard ratios(HR)with 95%CI for cardiovascular disease(CVD)death and all-cause death in associations with baseline lipid indicators.RESULTS A total of 4499 participants were recruited,and the mean levels of uric acid,body mass index,systolic blood pres-sure,diastolic blood pressure,fasting plasma glucose,total cholesterol(TC),triglyceride,and low-density lipoprotein cholesterol(LDL-C)showed an upward trend with the increasing remnant cholesterol(RC)quarters(Ptrend<0.05),while the downward tr-end was found in high-density lipoprotein cholesterol(HDL-C).During the total 36,596 person-years follow-up,the CVD mortal-ity and all-cause mortality during an average 8.13 years of follow-up was 3.87%(95%CI:3.30%-4.43%)and 14.83%(95%CI:13.79%-15.86%)with 174 CVD death participants and 667 all-cause death participants.After adjusting for confounders,the higher level of TC(HR=0.854,95%CI:0.730-0.997),LDL-C(HR=0.817,95%CI:0.680-0.982)and HDL-C(HR=0.443,95%CI:0.271-0.724)were associated with lower risk of CVD death,and the higher level of HDL-C(HR=0.637,95%CI:0.501-0.810)were associated with lower risk of all-cause death.The higher level of RC(HR=1.276,95%CI:1.010-1.613)increase the risk of CVD death.Com-pared with the normal lipid group,TC≥6.20 mmol/L group and LDL-C≥4.10 mmol/L group were no longer associated with lower risk of CVD death,while RC≥0.80 mmol/L group was still associated with higher risk of CVD death.In normal lipid gr-oup,the higher levels of TC,LDL-C and HDL-C were related with lower CVD death.CONCLUSIONS In community older adults,higher levels of TC and HDL-C were associated with lower CVD mortality in normal lipid reference range.Higher RC was associated with higher CVD mortality,which may be a better lipid indicator for es-timating the CVD death risk in older adults.