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...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.展开更多
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 primar...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.展开更多
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 ...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.展开更多
Cholesterol is a lipid that is an essential component of the membrane structure in mammals.Cholesterol homeostasis regulates vital activities of individual cells and governs the overall function of the mammalian body....Cholesterol is a lipid that is an essential component of the membrane structure in mammals.Cholesterol homeostasis regulates vital activities of individual cells and governs the overall function of the mammalian body.Cholesterol is mainly obtained through the biosynthesis of endogenous cholesterol and the intake of exogenous cholesterol.Cholesterol metabolism in tumor cells is abnormally active,and cholesterol and its metabolites(precursors and derivatives)play important roles in cancer proliferation,survival,invasion,metastasis,and the resistance to radiation.Preclinical studies have indicated that blocking cholesterol synthesis and uptake can reduce tumor progression and improve the response to anticancer treatment.Therapeutic strategies that target cholesterol synthesis,reduce plasma cholesterol levels,and prevent cholesterol esterification represent promising ways to improve the clinical outcome of cancer patients.展开更多
BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the gastrointestinal tract.Lipid metabolism,as an important part of material and energy circulation,is well known to play a crucial role in CRC.AIM To ex...BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the gastrointestinal tract.Lipid metabolism,as an important part of material and energy circulation,is well known to play a crucial role in CRC.AIM To explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC.METHODS We retrospectively collected 843 patients who had confirmed CRC and received surgical resection from 2013 to 2015 at the Cancer Hospital of the Chinese Academy of Medical Sciences as our research subjects.The levels of serum total cholesterol(TC),triglycerides,low-density lipoprotein cholesterol(LDL-C),highdensity lipoprotein cholesterol(HDL-C),LDL-C/HDL-C and clinical features were collected and statistically analyzed by SPSS.Then,we used the data from Oncomine to screen the differentially expressed genes(DEGs)of the cholesterol metabolism pathway in CRC and used Gene Expression Profiling Interactive Analysis to confirm the candidate DEGs.PrognoScan was used to analyze the prognostic value of the DEGs,and Search Tool for the Retrieval of Interacting Genes was used to construct the protein-protein interaction network of DEGs.RESULTS The serum HDL-C level in CRC patients was significantly correlated with tumor size,and patients whose tumor size was more than 5 cm had a lower serum HDL-C level(1.18±0.41 mmol/L vs 1.25±0.35 mmol/L,P<0.01)than their counterparts.In addition,TC/HDL(4.19±1.33 vs 3.93±1.26,P<0.01)and LDL-C/HDL-C(2.83±1.10 vs 2.61±0.96,P<0.01)were higher in patients with larger tumors.The levels of HDL-C(P<0.05),TC/HDL-C(P<0.01)and LDL-C/HDL-C(P<0.05)varied in different stages of CRC patients,and the differences were significant.We screened 14 differentially expressed genes(DEGs)of the cholesterol metabolism pathway in CRC and confirmed that lipoprotein receptor-related protein 8(LRP8),PCSK9,low-density lipoprotein receptor(LDLR),MBTPS2 and FDXR are upregulated,while ABCA1 and OSBPL1A are downregulated in cancer tissue.Higher expression of LDLR(HR=3.12,95%CI:1.77-5.49,P<0.001),ABCA1(HR=1.66,95%CI:1.11-2.48,P=0.012)and OSBPL1A(HR=1.38,95%CI:1.01-1.89,P=0.041)all yielded significantly poorer DFS outcomes.Higher expression of FDXR(HR=0.7,95%CI:0.47-1.05,P=0.002)was correlated with longer DFS.LDLR,ABCA1,OSBPL1A and FDXR were involved in many important cellular function pathways.CONCLUSION Serum HDL-C levels are associated with tumor size and stage in CRC patients.LRP8,PCSK9,LDLR,MBTPS2 and FDXR are upregulated,while ABCA1 and OSBPL1A are downregulated in CRC.Among them,LDLR,ABCA1,OSBPL1A and FDXR were valuable prognostic factors of DFS and were involved in important cellular function pathways.展开更多
The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that aff...The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein(LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X(Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers- such as cholesterol precursor sterols, plant sterols, and cholestanol- may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.展开更多
Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is in- dependent from that in peripheral tissues due to blood...Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is in- dependent from that in peripheral tissues due to blood- brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabo- lism with molecular mechanisms.展开更多
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 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.展开更多
Objective:To analyze the effect of Xuezhikang on the markers of the serum lipid levels of cholesterol synthesis and absorption in early menopausal women with hypercholesterolemia,and preliminarily explore its lipid-lo...Objective:To analyze the effect of Xuezhikang on the markers of the serum lipid levels of cholesterol synthesis and absorption in early menopausal women with hypercholesterolemia,and preliminarily explore its lipid-lowering mechanism.Methods:A total of 90 early menopausal women with hypercholesterolemia were enrolled from December,2014 to May,2016 from Beijing Anzhen Hospital,Capital Medical University,who were randomly allocated to receive Xuezhikang(1200 mg/d,orally)or atorvastatin(10 mg/d,orally)according to a random number table.Serum levels of some related biomarkers,including cholesterol synthesis markers(squalene,dihydrocholesterol,dehydrocholesterol,and lathosterol),and absorption markers(campesterol,stigmasterol,and sitosterol)as well as safety indices were obtained at baseline and after 8 weeks of the intervention.Results:Eight weeks after treatment,both Xuezhikang and atorvastatin significantly reduced the levels of total cholesterol,triglycerides,low density cholesterol compared to baseline(all P<0.01).Xuezhikang significantly reduced the levels of squalene,dehydrocholesterol and lathosterol compared to baseline(all P<0.01),but atorvastatin only significantly reduced the level of squalene(P<0.01),compared to baseline.All cholesterol absorption markers showed no significant differences before and after treatment(P>0.05),however,a more obvious downward trend was shown in the Xuezhikang group.In addition,all the safety indices showed no significant differences between the two groups.Although the creatinekinase level in the Xuezhikang group was significantly higher,it remained within the safe range.Conclusions:Xuezhikang may have more comprehensive effects on the markers of cholesterol synthesis and metabolism in early menopausal women with hypercholesterolemia through ergosterol and flavonoids in its"natural polypill."展开更多
Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemi...Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemia.Many metabolic-related genes and metabolites are essential to the progress and drug resistance of leukemia.Exploring potential therapeutical targets related to cholesterol homeostasis is a promising area.This review summarized the functions of cholesterol and its derived intermediate metabolites,and also discussed potential agents targeting this metabolic vulnerability in leukemia.展开更多
Background:Nonalcoholic fatty liver disease(NAFLD)is an independent risk factor for severe acute pancreatitis(AP).The underlying mechanism remains unclear.We sought to determine how bacterial translocation and cholest...Background:Nonalcoholic fatty liver disease(NAFLD)is an independent risk factor for severe acute pancreatitis(AP).The underlying mechanism remains unclear.We sought to determine how bacterial translocation and cholesterol metabolism in the liver and pancreas affect the severity of AP in NAFLD mice.Methods:C57BL/6N mice were fed on a high-fat diet(HFD)to generate the NAFLD model,and mice in the control group were provided with a normal diet(ND).After being anesthetized with ketamine/xylazine,mice got a retrograde infusion of taurocholic acid sodium into the pancreatic duct to induce AP,and sham operation(SO)was used as control.Serum amylase and Schmidt’s pathological score system were used to evaluate AP severity.Bacterial loads,total cholesterol level,and cholesterol metabolic-associated molecules[low-density lipoprotein receptor(LDLR)and ATP-binding cassette transporter A1(ABCA1)]were analyzed in the liver and pancreas.Results:Compared with the ND-AP group,mice in the HFD-AP group had severer pancreatitis,manifested with higher serum amylase levels and higher AP pathologic scores,especially the inflammation and hemorrhage scores.Compared with the HFD-SO group and ND-AP group,bacterial loads in the liver and pancreas were significantly higher in the HFD-AP group.Mice in the HFD-AP group showed a decreased LDLR expression and an increased ABCA1 expression in the pancreas,although there was no significant difference in pancreas total cholesterol between the HFD-AP group and the ND-AP group.Conclusions:NAFLD aggravates AP via increasing bacterial translocation in the liver and pancreas and affecting pancreas cholesterol metabolism in mice.展开更多
AIM To assess potential contributions of biliary IgA for crystal agglomeration into gallstones, we visualized cholesterol crystal binding of biliary IgA.METHODS Crystal-binding biliary proteins were extracted from hum...AIM To assess potential contributions of biliary IgA for crystal agglomeration into gallstones, we visualized cholesterol crystal binding of biliary IgA.METHODS Crystal-binding biliary proteins were extracted from human gallbladder bile using lectin affinity chromatography. Biliary IgA was isolated from the bound protein fraction by immunoaffinity chromatography. Pure cholesterol monohydrate crystals were incubated with biliary IgA and fluoresceine isothiocyanate (FITC)-conjugated anti-lgA at 37C. Samples were examined under polarizing and fluorescence light microscopy with digital image processing.RESULTS Binding of biliary IgA to cholesterol monohydrate crystals could be visualized with FITC-conjugated anti-lgA antibodies. Peak fluorescence occurred at crystal edges and dislocations. Controls without biliary IgA or with biliary IgG showed no significant fluorescence.CONCLUSION Fluorescence light microscopy provided evidence for cholesterol crystal binding of biliary IgA. Cholesterol crystalbinding proteins like IgA might be important mediators of crystal agglomeration and growth of cholesterol gallstones by modifying the evolving crystal structures in vivo.展开更多
Lathosterolosis is a very rare autosomal recessive cholesterol metabolism disorder. The disease manifests itself with developmental and mental delays, learning disabilities, microcephaly, facial dysmorphism, bilateral...Lathosterolosis is a very rare autosomal recessive cholesterol metabolism disorder. The disease manifests itself with developmental and mental delays, learning disabilities, microcephaly, facial dysmorphism, bilateral cataracts, and skeletal defects. It is caused by the deficiency of the enzyme sterol-C5-desaturase, which is involved in cholesterol biosynthesis. This deficiency prevents the synthesis of cholesterol, which acts as a precursor for lipid, bile acids, and steroid hormones. Until 2020, only 7 cases had been reported. In this case report, it was aimed to plan and implement the nursing care of a 2-year-old boy diagnosed with lathosterolosis with the diagnoses of the North American Nursing Diagnostic Association (NANDA).展开更多
The roles of dietary cholesterol in fish physiology are currently contradictory.The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish.The present study investigated the met...The roles of dietary cholesterol in fish physiology are currently contradictory.The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish.The present study investigated the metabolic responses to high cholesterol intake in Nile tilapia(Oreochromis niloticus),which were fed with four cholesterol-contained diets(0.8,1.6,2.4 and 3.2%)and a control diet for eight weeks.All fish-fed cholesterol diets showed increased body weight,but accumulated cholesterol(the peak level was in the 1.6%cholesterol group).Then,we selected 1.6%cholesterol and control diets for further analysis.The high cholesterol diet impaired liver function and reduced mitochondria number in fish.Furthermore,high cholesterol intake triggered protective adaptation via(1)inhibiting endogenous cholesterol synthesis,(2)elevating the expression of genes related to cholesterol esterification and efflux,and(3)promoting chenodeoxycholic acid synthesis and efflux.Accordingly,high cholesterol intake reshaped the fish gut microbiome by increasing the abundance of Lactobacillus spp.and Mycobacterium spp.,both of which are involved in cholesterol and/or bile acids catabolism.Moreover,high cholesterol intake inhibited lipid catabolic activities through mitochondrialβ-oxidation,and lysosome-mediated lipophagy,and depressed insulin signaling sensitivity.Protein catabolism was elevated as a compulsory response to maintain energy homeostasis.Therefore,although high cholesterol intake promoted growth,it led to metabolic disorders in fish.For the first time,this study provides evidence for the systemic metabolic response to high cholesterol intake in fish.This knowledge contributes to an understanding of the metabolic syndromes caused by high cholesterol intake or deposition in fish.展开更多
Bad, round Statins and ezetimibe have been reported to change the balance of cholesterol metabolism, but few studies have been performed on Chinese patients. The aim of this study was to evaluate changes in cholestero...Bad, round Statins and ezetimibe have been reported to change the balance of cholesterol metabolism, but few studies have been performed on Chinese patients. The aim of this study was to evaluate changes in cholesterol metabolism markers in patients with coronary heart disease. Methods Forty-five patients with coronary heart disease were treated with 20 mg/d of simvastatin for four weeks. Subjects were then divided into two different therapy groups according to whether they reached the target values for total cholesterol and low density lipoprotein cholesterol level. Patients who reached the target values remained on simvastatin and those who did not reach the target values took a combination of simvastatin plus 10 mg/d ezetimibe until the 12th week. The concentrations of cholesterol synthesis markers (lathosterol and desmosterol) and absorption markers (campesterol and sitosterol) were measured on the 1st, 4th, and 12th week of the study by gas chromatography. Results After treatment with simvastatin for four weeks, the levels of total cholesterol and low density lipoprotein cholesterol decreased significantly compared to levels measured during the 1st week (P 〈0.05). On the 12th week the levels of total cholesterol and low density lipoprotein cholesterol had decreased significantly (P 〈0.001) compared to levels during the 4th week. By the 12th week the levels of campesterol and sitosterol in the combination group had decreased significantly (P〈0.05) compared with levels measured during the 4th week. Conclusions Coronary heart disease patients with high cholesterol synthesis at baseline might gain a greater benefit from simvastatin treatment. Combination therapy with simvastatin plus ezetimibe in patients with low cholesterol synthesis at baseline might increase the success rate of lipid-lowering throuah decreasing the absorption of cholesterol.展开更多
Chronic hepatitis B(CHB)infection remains a serious public health problem worldwide;however,the relationship between cholesterol levels and CHB remains unclear.We isolated peripheral blood mononuclear cells from healt...Chronic hepatitis B(CHB)infection remains a serious public health problem worldwide;however,the relationship between cholesterol levels and CHB remains unclear.We isolated peripheral blood mononuclear cells from healthy blood donors and CHB patients to analyze free cholesterol levels,lipid raft formation,and cholesterol metabolism-related pathways.Hepatitis B virus(HBV)-carrier mice were generated and used to confirm changes in cholesterol metabolism and cell-surface lipid raft formation in dendritic cells(DCs)in the context of CHB.Additionally,HBV-carrier mice were immunized with a recombinant HBV vaccine(rHBVvac)combined with lipophilic statins and evaluated for vaccine efficacy against HBV.Serum samples were analyzed for HBsAg,anti-HBs,and alanine aminotransferase levels,and liver samples were evaluated for HBV DNA and RNA and HBcAg.CHB reduced free cholesterol levels and suppressed lipid raft formation on DCs in patients with CHB and HBV-carrier mice,whereas administration of lipophilic statins promoted free cholesterol accumulation and restored lipid rafts on DCs accompanied by an enhanced antigen-presentation ability in vitro and in vivo.Cholesterol accumulation on DCs improved the rHBVvac-mediated elimination of serum HBV DNA and intrahepatic HBV DNA,HBV RNA,and HBcAg and promoted the rHBVvac-mediated generation and polyfunctionality of HBV-specific CD11a^(hi) CD8α^(lo) cells,induction of the development of memory responses against HBV reinfection,and seroconversion from HBsAg to anti-HBs.The results demonstrated the important role of cholesterol levels in DC dysfunction during CHB,suggesting that strategies to increase cholesterol accumulation on DCs might enhance therapeutic vaccine efficacy against HBV and support development toward clinical CHB treatment.展开更多
As an essential part of adaptive immunity,T cells coordinate the immune responses against pathogens and cancer cells.Lipid metabolism has emerged as a key regulator for the activation,differentiation,and effector func...As an essential part of adaptive immunity,T cells coordinate the immune responses against pathogens and cancer cells.Lipid metabolism has emerged as a key regulator for the activation,differentiation,and effector functions of T cells.Therefore,uncovering the molecular mechanisms by which lipid metabolism dictates T cell biology is of vital importance.The tumor microenvironment is a hostile milieu,i.e.often characterized by nutrient restriction.In this environment,various cells,such as T cells and cancer cells,reprogram their metabolism,including their lipid metabolism,to meet their energy and functional needs.Here,we review the participation of fatty acid and cholesterol metabolism homeostasis in orchestrating T cell biology.We demonstrate how the tumor microenvironment reshapes the lipid metabolism in T cells.Importantly,we highlight the current cancer therapeutic interventions that target fatty acid and cholesterol metabolism of T cells.By offering a holistic understanding of how lipid metabolic adaption by T cells facilitates their immunosurveillance in the tumor microenvironment,we believe this review and the future studies might inspire the next-generation immunotherapies.展开更多
After leaving the testis,mammalian sperm undergo a sequential maturation process in the epididymis followed by capacitation during their movement through the female reproductive tract.These phenotypic changes are asso...After leaving the testis,mammalian sperm undergo a sequential maturation process in the epididymis followed by capacitation during their movement through the female reproductive tract.These phenotypic changes are associated with modification of protein phosphorylation and membrane remodeling,which is requisite for sperm to acquire forward motility and induce fertilization.However,the molecular mechanisms underlying sperm maturation and capacitation are still not fully understood.Herein,we show that PPP3R2,a testis-specific regulatory subunit of protein phosphatase 3(an isoform of calcineurin in the testis),is essential for sperm maturation and capacitation.Knockout of Ppp3r2 in mice leads to male sterility due to sperm motility impairment and morphological defects.One very noteworthy change includes increases in sperm membrane stiffness.Moreover,PPP3R2 regulates sperm maturation and capacitation via(i)modulation of membrane diffusion barrier function at the annulus and(ii)facilitation of cholesterol efflux during sperm capacitation.Taken together,PPP3R2 plays a critical role in modulating cholesterol efflux and mediating the dynamic control of membrane remodeling during sperm maturation and capacitation.展开更多
Lipid Droplets(LDs)are emerging as crucial players in colon cancer development and maintenance.Their expression has been associated with high tumorigenicity in Cancer Stem Cells(CSCs),so that they have been proposed a...Lipid Droplets(LDs)are emerging as crucial players in colon cancer development and maintenance.Their expression has been associated with high tumorigenicity in Cancer Stem Cells(CSCs),so that they have been proposed as a new functional marker in Colorectal Cancer Stem Cells(CR-CSCs).They are also indirectly involved in the modulation of the tumor microenvironment through the production of pro-inflammatory molecules.There is growing evidence that a possible connection between metabolic alterations and malignant transformation exists,although the effects of nutrients,primarily glucose,on the CSC behavior are still mostly unexplored.Glucose is an essential fuel for cancer cells,and the connections with LDs in the healthy and CSC populations merit to be more deeply investigated.Here,we showed that a high glucose concentration activated the PI3K/AKT pathway and increased the expression of CD133 and CD44v6 CSC markers.Additionally,glucose was responsible for the increased amount of Reactive Oxygen Species(ROS)and LDs in both healthy and CR-CSC samples.We also investigated the gene modulations following the HG treatment and found out that the healthy cell gene profile was the most affected.Lastly,Atorvastatin,a lipidlowering drug,induced the highest mortality on CR-CSCs without affecting the healthy counterpart.展开更多
The MBOATenzyme family,identified in 2000,comprises 11 genes in the human genome that participate in a variety of biological processes.MBOAT enzymes contain multiple transmembrane domains and share two active site res...The MBOATenzyme family,identified in 2000,comprises 11 genes in the human genome that participate in a variety of biological processes.MBOAT enzymes contain multiple transmembrane domains and share two active site residues,histidine and asparagine.Several MBOAT members are drug targets for major human diseases,including atherosclerosis,obesity,Alzheimer disease,and viral infections.Here we review the historical aspects of MBOAT enzymes,classify them biochemically into 3 subgroups,and describe the essential features of each member.展开更多
基金funded in part by grants from the National Natural Science Foundation of China (No.31930105)National Key Research and Development Program of China (2022YFF1000204)China Agriculture Research Systems (CARS-40)。
文摘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.
基金financially supported by the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)China Postdoctoral Science Foundation,No.2022M711733(to ZZ)+2 种基金the National Natural Science Foundation of China,No.82160920(to ZZ)Hebei Postdoctoral Scientific Research Project,No.B2022003040(to ZZ)Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine(to WP)。
文摘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.
基金supported by the National Natural Science Foundation of China,No.82072110Suzhou Municipal Science and Technology Bureau,No.SKJY2021046+1 种基金Shanghai Key Lab of Forensic Medicine&Key Lab of Forensic Science,Ministry of Justice,China(Academy of Forensic Science),No.KF202201a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(all to TW).
文摘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.
基金supported by grants from the Project of Sichuan Science and Technology Department(No.2021YJ0010)the Sichuan Natural Science Foundation(No.2023NSFC0712).
文摘Cholesterol is a lipid that is an essential component of the membrane structure in mammals.Cholesterol homeostasis regulates vital activities of individual cells and governs the overall function of the mammalian body.Cholesterol is mainly obtained through the biosynthesis of endogenous cholesterol and the intake of exogenous cholesterol.Cholesterol metabolism in tumor cells is abnormally active,and cholesterol and its metabolites(precursors and derivatives)play important roles in cancer proliferation,survival,invasion,metastasis,and the resistance to radiation.Preclinical studies have indicated that blocking cholesterol synthesis and uptake can reduce tumor progression and improve the response to anticancer treatment.Therapeutic strategies that target cholesterol synthesis,reduce plasma cholesterol levels,and prevent cholesterol esterification represent promising ways to improve the clinical outcome of cancer patients.
文摘BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the gastrointestinal tract.Lipid metabolism,as an important part of material and energy circulation,is well known to play a crucial role in CRC.AIM To explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC.METHODS We retrospectively collected 843 patients who had confirmed CRC and received surgical resection from 2013 to 2015 at the Cancer Hospital of the Chinese Academy of Medical Sciences as our research subjects.The levels of serum total cholesterol(TC),triglycerides,low-density lipoprotein cholesterol(LDL-C),highdensity lipoprotein cholesterol(HDL-C),LDL-C/HDL-C and clinical features were collected and statistically analyzed by SPSS.Then,we used the data from Oncomine to screen the differentially expressed genes(DEGs)of the cholesterol metabolism pathway in CRC and used Gene Expression Profiling Interactive Analysis to confirm the candidate DEGs.PrognoScan was used to analyze the prognostic value of the DEGs,and Search Tool for the Retrieval of Interacting Genes was used to construct the protein-protein interaction network of DEGs.RESULTS The serum HDL-C level in CRC patients was significantly correlated with tumor size,and patients whose tumor size was more than 5 cm had a lower serum HDL-C level(1.18±0.41 mmol/L vs 1.25±0.35 mmol/L,P<0.01)than their counterparts.In addition,TC/HDL(4.19±1.33 vs 3.93±1.26,P<0.01)and LDL-C/HDL-C(2.83±1.10 vs 2.61±0.96,P<0.01)were higher in patients with larger tumors.The levels of HDL-C(P<0.05),TC/HDL-C(P<0.01)and LDL-C/HDL-C(P<0.05)varied in different stages of CRC patients,and the differences were significant.We screened 14 differentially expressed genes(DEGs)of the cholesterol metabolism pathway in CRC and confirmed that lipoprotein receptor-related protein 8(LRP8),PCSK9,low-density lipoprotein receptor(LDLR),MBTPS2 and FDXR are upregulated,while ABCA1 and OSBPL1A are downregulated in cancer tissue.Higher expression of LDLR(HR=3.12,95%CI:1.77-5.49,P<0.001),ABCA1(HR=1.66,95%CI:1.11-2.48,P=0.012)and OSBPL1A(HR=1.38,95%CI:1.01-1.89,P=0.041)all yielded significantly poorer DFS outcomes.Higher expression of FDXR(HR=0.7,95%CI:0.47-1.05,P=0.002)was correlated with longer DFS.LDLR,ABCA1,OSBPL1A and FDXR were involved in many important cellular function pathways.CONCLUSION Serum HDL-C levels are associated with tumor size and stage in CRC patients.LRP8,PCSK9,LDLR,MBTPS2 and FDXR are upregulated,while ABCA1 and OSBPL1A are downregulated in CRC.Among them,LDLR,ABCA1,OSBPL1A and FDXR were valuable prognostic factors of DFS and were involved in important cellular function pathways.
文摘The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein(LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X(Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers- such as cholesterol precursor sterols, plant sterols, and cholestanol- may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.
文摘Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is in- dependent from that in peripheral tissues due to blood- brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabo- lism with molecular mechanisms.
基金supported by the National Natural Science Foundation of ChinaNo.81971826 (to AG)+5 种基金the China Postdoctoral Science FoundationNo.2020M681 689 (to YH)the Scientific Research Project of The Health Commission of Jiangsu ProvinceNo.ZDB2020003 (to AG)the Basic Scientific Research Projects of NantongNo.JC2020041 (to YH)
文摘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.
基金Supported by National Natural Science Foundation of China(No.81703932)Beijing Natural Science Foundation(No.7144205)+2 种基金The Youth Talent Fund of Beijing Municipal Bureau of Health Administration Grants(No.QML20190605)Beijing Science and Technology Development Fund Project of Traditional Chinese Medicine(No.JJ-2020-01)Science and Technology Plan of Chaoyang District,Beijing(No.CYSF2027)。
文摘Objective:To analyze the effect of Xuezhikang on the markers of the serum lipid levels of cholesterol synthesis and absorption in early menopausal women with hypercholesterolemia,and preliminarily explore its lipid-lowering mechanism.Methods:A total of 90 early menopausal women with hypercholesterolemia were enrolled from December,2014 to May,2016 from Beijing Anzhen Hospital,Capital Medical University,who were randomly allocated to receive Xuezhikang(1200 mg/d,orally)or atorvastatin(10 mg/d,orally)according to a random number table.Serum levels of some related biomarkers,including cholesterol synthesis markers(squalene,dihydrocholesterol,dehydrocholesterol,and lathosterol),and absorption markers(campesterol,stigmasterol,and sitosterol)as well as safety indices were obtained at baseline and after 8 weeks of the intervention.Results:Eight weeks after treatment,both Xuezhikang and atorvastatin significantly reduced the levels of total cholesterol,triglycerides,low density cholesterol compared to baseline(all P<0.01).Xuezhikang significantly reduced the levels of squalene,dehydrocholesterol and lathosterol compared to baseline(all P<0.01),but atorvastatin only significantly reduced the level of squalene(P<0.01),compared to baseline.All cholesterol absorption markers showed no significant differences before and after treatment(P>0.05),however,a more obvious downward trend was shown in the Xuezhikang group.In addition,all the safety indices showed no significant differences between the two groups.Although the creatinekinase level in the Xuezhikang group was significantly higher,it remained within the safe range.Conclusions:Xuezhikang may have more comprehensive effects on the markers of cholesterol synthesis and metabolism in early menopausal women with hypercholesterolemia through ergosterol and flavonoids in its"natural polypill."
基金supported by National Natural Science Foundation of China to H.Z.and L.Z.(Grant No.81770184 and 81800174).
文摘Leukemia is a common hematological malignancy with overall poor prognosis.Novel therapies are needed to improve the outcome of leukemia patients.Cholesterol metabolism reprogramming is a featured alteration in leukemia.Many metabolic-related genes and metabolites are essential to the progress and drug resistance of leukemia.Exploring potential therapeutical targets related to cholesterol homeostasis is a promising area.This review summarized the functions of cholesterol and its derived intermediate metabolites,and also discussed potential agents targeting this metabolic vulnerability in leukemia.
基金This study was supported by grants from the National Nat-ural Science Foundation of China(82070539 and 81873549)the Youth Innovation Foundation of Aerospace Center Hospital(2021QN02).
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is an independent risk factor for severe acute pancreatitis(AP).The underlying mechanism remains unclear.We sought to determine how bacterial translocation and cholesterol metabolism in the liver and pancreas affect the severity of AP in NAFLD mice.Methods:C57BL/6N mice were fed on a high-fat diet(HFD)to generate the NAFLD model,and mice in the control group were provided with a normal diet(ND).After being anesthetized with ketamine/xylazine,mice got a retrograde infusion of taurocholic acid sodium into the pancreatic duct to induce AP,and sham operation(SO)was used as control.Serum amylase and Schmidt’s pathological score system were used to evaluate AP severity.Bacterial loads,total cholesterol level,and cholesterol metabolic-associated molecules[low-density lipoprotein receptor(LDLR)and ATP-binding cassette transporter A1(ABCA1)]were analyzed in the liver and pancreas.Results:Compared with the ND-AP group,mice in the HFD-AP group had severer pancreatitis,manifested with higher serum amylase levels and higher AP pathologic scores,especially the inflammation and hemorrhage scores.Compared with the HFD-SO group and ND-AP group,bacterial loads in the liver and pancreas were significantly higher in the HFD-AP group.Mice in the HFD-AP group showed a decreased LDLR expression and an increased ABCA1 expression in the pancreas,although there was no significant difference in pancreas total cholesterol between the HFD-AP group and the ND-AP group.Conclusions:NAFLD aggravates AP via increasing bacterial translocation in the liver and pancreas and affecting pancreas cholesterol metabolism in mice.
文摘AIM To assess potential contributions of biliary IgA for crystal agglomeration into gallstones, we visualized cholesterol crystal binding of biliary IgA.METHODS Crystal-binding biliary proteins were extracted from human gallbladder bile using lectin affinity chromatography. Biliary IgA was isolated from the bound protein fraction by immunoaffinity chromatography. Pure cholesterol monohydrate crystals were incubated with biliary IgA and fluoresceine isothiocyanate (FITC)-conjugated anti-lgA at 37C. Samples were examined under polarizing and fluorescence light microscopy with digital image processing.RESULTS Binding of biliary IgA to cholesterol monohydrate crystals could be visualized with FITC-conjugated anti-lgA antibodies. Peak fluorescence occurred at crystal edges and dislocations. Controls without biliary IgA or with biliary IgG showed no significant fluorescence.CONCLUSION Fluorescence light microscopy provided evidence for cholesterol crystal binding of biliary IgA. Cholesterol crystalbinding proteins like IgA might be important mediators of crystal agglomeration and growth of cholesterol gallstones by modifying the evolving crystal structures in vivo.
文摘Lathosterolosis is a very rare autosomal recessive cholesterol metabolism disorder. The disease manifests itself with developmental and mental delays, learning disabilities, microcephaly, facial dysmorphism, bilateral cataracts, and skeletal defects. It is caused by the deficiency of the enzyme sterol-C5-desaturase, which is involved in cholesterol biosynthesis. This deficiency prevents the synthesis of cholesterol, which acts as a precursor for lipid, bile acids, and steroid hormones. Until 2020, only 7 cases had been reported. In this case report, it was aimed to plan and implement the nursing care of a 2-year-old boy diagnosed with lathosterolosis with the diagnoses of the North American Nursing Diagnostic Association (NANDA).
基金This work was supported by the National Key R&D Program of China(2018YFD0900400).
文摘The roles of dietary cholesterol in fish physiology are currently contradictory.The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish.The present study investigated the metabolic responses to high cholesterol intake in Nile tilapia(Oreochromis niloticus),which were fed with four cholesterol-contained diets(0.8,1.6,2.4 and 3.2%)and a control diet for eight weeks.All fish-fed cholesterol diets showed increased body weight,but accumulated cholesterol(the peak level was in the 1.6%cholesterol group).Then,we selected 1.6%cholesterol and control diets for further analysis.The high cholesterol diet impaired liver function and reduced mitochondria number in fish.Furthermore,high cholesterol intake triggered protective adaptation via(1)inhibiting endogenous cholesterol synthesis,(2)elevating the expression of genes related to cholesterol esterification and efflux,and(3)promoting chenodeoxycholic acid synthesis and efflux.Accordingly,high cholesterol intake reshaped the fish gut microbiome by increasing the abundance of Lactobacillus spp.and Mycobacterium spp.,both of which are involved in cholesterol and/or bile acids catabolism.Moreover,high cholesterol intake inhibited lipid catabolic activities through mitochondrialβ-oxidation,and lysosome-mediated lipophagy,and depressed insulin signaling sensitivity.Protein catabolism was elevated as a compulsory response to maintain energy homeostasis.Therefore,although high cholesterol intake promoted growth,it led to metabolic disorders in fish.For the first time,this study provides evidence for the systemic metabolic response to high cholesterol intake in fish.This knowledge contributes to an understanding of the metabolic syndromes caused by high cholesterol intake or deposition in fish.
基金This study was supported by grants from the National Natural Science Foundation of China,Natural Science Foundation of Beijing
文摘Bad, round Statins and ezetimibe have been reported to change the balance of cholesterol metabolism, but few studies have been performed on Chinese patients. The aim of this study was to evaluate changes in cholesterol metabolism markers in patients with coronary heart disease. Methods Forty-five patients with coronary heart disease were treated with 20 mg/d of simvastatin for four weeks. Subjects were then divided into two different therapy groups according to whether they reached the target values for total cholesterol and low density lipoprotein cholesterol level. Patients who reached the target values remained on simvastatin and those who did not reach the target values took a combination of simvastatin plus 10 mg/d ezetimibe until the 12th week. The concentrations of cholesterol synthesis markers (lathosterol and desmosterol) and absorption markers (campesterol and sitosterol) were measured on the 1st, 4th, and 12th week of the study by gas chromatography. Results After treatment with simvastatin for four weeks, the levels of total cholesterol and low density lipoprotein cholesterol decreased significantly compared to levels measured during the 1st week (P 〈0.05). On the 12th week the levels of total cholesterol and low density lipoprotein cholesterol had decreased significantly (P 〈0.001) compared to levels during the 4th week. By the 12th week the levels of campesterol and sitosterol in the combination group had decreased significantly (P〈0.05) compared with levels measured during the 4th week. Conclusions Coronary heart disease patients with high cholesterol synthesis at baseline might gain a greater benefit from simvastatin treatment. Combination therapy with simvastatin plus ezetimibe in patients with low cholesterol synthesis at baseline might increase the success rate of lipid-lowering throuah decreasing the absorption of cholesterol.
基金supported by the National Key Research and Development Programme (2021YFC2300603)the National Postdoctoral Programme for Innovative Talents (No.BX20190192)+1 种基金the China Postdoctoral Science Foundation (No.2020M672064)the National Science Foundation for Young Scientists of China (No.82001687).
文摘Chronic hepatitis B(CHB)infection remains a serious public health problem worldwide;however,the relationship between cholesterol levels and CHB remains unclear.We isolated peripheral blood mononuclear cells from healthy blood donors and CHB patients to analyze free cholesterol levels,lipid raft formation,and cholesterol metabolism-related pathways.Hepatitis B virus(HBV)-carrier mice were generated and used to confirm changes in cholesterol metabolism and cell-surface lipid raft formation in dendritic cells(DCs)in the context of CHB.Additionally,HBV-carrier mice were immunized with a recombinant HBV vaccine(rHBVvac)combined with lipophilic statins and evaluated for vaccine efficacy against HBV.Serum samples were analyzed for HBsAg,anti-HBs,and alanine aminotransferase levels,and liver samples were evaluated for HBV DNA and RNA and HBcAg.CHB reduced free cholesterol levels and suppressed lipid raft formation on DCs in patients with CHB and HBV-carrier mice,whereas administration of lipophilic statins promoted free cholesterol accumulation and restored lipid rafts on DCs accompanied by an enhanced antigen-presentation ability in vitro and in vivo.Cholesterol accumulation on DCs improved the rHBVvac-mediated elimination of serum HBV DNA and intrahepatic HBV DNA,HBV RNA,and HBcAg and promoted the rHBVvac-mediated generation and polyfunctionality of HBV-specific CD11a^(hi) CD8α^(lo) cells,induction of the development of memory responses against HBV reinfection,and seroconversion from HBsAg to anti-HBs.The results demonstrated the important role of cholesterol levels in DC dysfunction during CHB,suggesting that strategies to increase cholesterol accumulation on DCs might enhance therapeutic vaccine efficacy against HBV and support development toward clinical CHB treatment.
基金C.X.is funded by National Natural Science Foundation of China(92057201,92157301).
文摘As an essential part of adaptive immunity,T cells coordinate the immune responses against pathogens and cancer cells.Lipid metabolism has emerged as a key regulator for the activation,differentiation,and effector functions of T cells.Therefore,uncovering the molecular mechanisms by which lipid metabolism dictates T cell biology is of vital importance.The tumor microenvironment is a hostile milieu,i.e.often characterized by nutrient restriction.In this environment,various cells,such as T cells and cancer cells,reprogram their metabolism,including their lipid metabolism,to meet their energy and functional needs.Here,we review the participation of fatty acid and cholesterol metabolism homeostasis in orchestrating T cell biology.We demonstrate how the tumor microenvironment reshapes the lipid metabolism in T cells.Importantly,we highlight the current cancer therapeutic interventions that target fatty acid and cholesterol metabolism of T cells.By offering a holistic understanding of how lipid metabolic adaption by T cells facilitates their immunosurveillance in the tumor microenvironment,we believe this review and the future studies might inspire the next-generation immunotherapies.
基金supported by grants from the National Natural Science Foundation of China(81571487,81701503,and 81971437)Science and Technology Commission of Shanghai Municipality(16ZR1418600).
文摘After leaving the testis,mammalian sperm undergo a sequential maturation process in the epididymis followed by capacitation during their movement through the female reproductive tract.These phenotypic changes are associated with modification of protein phosphorylation and membrane remodeling,which is requisite for sperm to acquire forward motility and induce fertilization.However,the molecular mechanisms underlying sperm maturation and capacitation are still not fully understood.Herein,we show that PPP3R2,a testis-specific regulatory subunit of protein phosphatase 3(an isoform of calcineurin in the testis),is essential for sperm maturation and capacitation.Knockout of Ppp3r2 in mice leads to male sterility due to sperm motility impairment and morphological defects.One very noteworthy change includes increases in sperm membrane stiffness.Moreover,PPP3R2 regulates sperm maturation and capacitation via(i)modulation of membrane diffusion barrier function at the annulus and(ii)facilitation of cholesterol efflux during sperm capacitation.Taken together,PPP3R2 plays a critical role in modulating cholesterol efflux and mediating the dynamic control of membrane remodeling during sperm maturation and capacitation.
基金This study was supported by Italian Association for Cancer Research(AIRC)and from the European Union’s Horizon 2020 Research And Innovation Programme under the Marie Skłodowska-Curie grant agreement No 800924This work was also supported by AIRC(5x1000 Clinical Oncology Extension Program 9979 and IG 16746).The authors acknowledge financial support from King Abdullah University of Science and Technology for OCRF-2014-CRG and OCRF-2016-CRG grants and from Piedmont Region through European Funds for Regional Development(“Food Digital Monitoring”project)This work is dedicated to the memory of our beloved Prof.Giovanni Morrone。
文摘Lipid Droplets(LDs)are emerging as crucial players in colon cancer development and maintenance.Their expression has been associated with high tumorigenicity in Cancer Stem Cells(CSCs),so that they have been proposed as a new functional marker in Colorectal Cancer Stem Cells(CR-CSCs).They are also indirectly involved in the modulation of the tumor microenvironment through the production of pro-inflammatory molecules.There is growing evidence that a possible connection between metabolic alterations and malignant transformation exists,although the effects of nutrients,primarily glucose,on the CSC behavior are still mostly unexplored.Glucose is an essential fuel for cancer cells,and the connections with LDs in the healthy and CSC populations merit to be more deeply investigated.Here,we showed that a high glucose concentration activated the PI3K/AKT pathway and increased the expression of CD133 and CD44v6 CSC markers.Additionally,glucose was responsible for the increased amount of Reactive Oxygen Species(ROS)and LDs in both healthy and CR-CSC samples.We also investigated the gene modulations following the HG treatment and found out that the healthy cell gene profile was the most affected.Lastly,Atorvastatin,a lipidlowering drug,induced the highest mortality on CR-CSCs without affecting the healthy counterpart.
文摘The MBOATenzyme family,identified in 2000,comprises 11 genes in the human genome that participate in a variety of biological processes.MBOAT enzymes contain multiple transmembrane domains and share two active site residues,histidine and asparagine.Several MBOAT members are drug targets for major human diseases,including atherosclerosis,obesity,Alzheimer disease,and viral infections.Here we review the historical aspects of MBOAT enzymes,classify them biochemically into 3 subgroups,and describe the essential features of each member.