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
The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane pr...The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.展开更多
目的探讨槲皮素对高脂膳食诱导的载脂蛋白E敲除(apolipoprotein E knockout,ApoE KO)小鼠动脉粥样硬化(atherosclerosis,AS)的保护效应及其对巨噬细胞胆固醇稳态的调控作用机制。方法雌性成年ApoE KO小鼠45只随机分为3组:普通饲料组、...目的探讨槲皮素对高脂膳食诱导的载脂蛋白E敲除(apolipoprotein E knockout,ApoE KO)小鼠动脉粥样硬化(atherosclerosis,AS)的保护效应及其对巨噬细胞胆固醇稳态的调控作用机制。方法雌性成年ApoE KO小鼠45只随机分为3组:普通饲料组、高脂饲料组、高脂饲料+槲皮素组,持续喂养16周。检测血脂水平、主动脉斑块形成情况及胆固醇稳态调控相关基因表达水平。建立RAW264.7巨噬细胞泡沫化模型并进行槲皮素干预,检测巨噬细胞胆固醇蓄积情况及胆固醇稳态调控相关蛋白表达水平。结果槲皮素可有效改善ApoE KO小鼠AS斑块损伤并降低其血脂水平;通过上调巨噬细胞CYP27A1表达,抑制CD36介导的胆固醇摄取,并增加LXRα-ABCA1/G1信号通路介导的胆固醇输出,有效降低巨噬细胞泡沫化水平。结论槲皮素可通过CYP27A1/LXRα信号通路调控巨噬细胞胆固醇稳态,发挥AS保护作用。展开更多
Cholesterol, being the starting point of steroid hormone synthesis, is a long known modulator of both female and male reproductive physiology especially at the level of the gonads and the impact cholesterol has on gam...Cholesterol, being the starting point of steroid hormone synthesis, is a long known modulator of both female and male reproductive physiology especially at the level of the gonads and the impact cholesterol has on gametogenesis. Less is known about the effects cholesterol homeostasis may have on postgonadic reproductive functions. Lately, several data have been reported showing how imbalanced cholesterol levels may particularly affect the post-testicular events of sperm maturation that lead to fully fertile male gametes. This review will focus on that aspect and essentially centers on how cholesterol is important for the physiology of the mammalian epididymis and spermatozoa.展开更多
胆固醇稳态对细胞功能和机体健康至关重要,胆固醇调节元件结合蛋白2(sterol-regulatory element binding protein 2,SREBP2)是维持胆固醇稳态的关键调控因子,是一种位于细胞内质网的胆固醇敏感调节器。SREBP2的表达和功能主要受三个水...胆固醇稳态对细胞功能和机体健康至关重要,胆固醇调节元件结合蛋白2(sterol-regulatory element binding protein 2,SREBP2)是维持胆固醇稳态的关键调控因子,是一种位于细胞内质网的胆固醇敏感调节器。SREBP2的表达和功能主要受三个水平的调控:(1)SREBF2基因的转录调控,(2)SREBP2蛋白的转运与剪切调控,(3)nSREBP2的修饰及功能调控。该文系统地对上述三个阶段调控的研究进展及其在代谢性疾病中的作用进行了综述,这将为靶向SREBP2研究胆固醇代谢及其代谢异常相关疾病的治疗提供理论参考。展开更多
Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles o...Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.展开更多
Objective:To clarify the anti-depressive potential mechanisms of Kaixin Powder(KP),a drug that helps to prevent and treat depression and other mentaldiseases,from genome-wide transcriptome profiling.Methods:Transcript...Objective:To clarify the anti-depressive potential mechanisms of Kaixin Powder(KP),a drug that helps to prevent and treat depression and other mentaldiseases,from genome-wide transcriptome profiling.Methods:Transcriptome and KEGG pathway analysis were conducted on the hippocampus of depressed rats,then the differentially expressed genes were validated and serum concentration of lipid parameters were identified by enzymatic assays.Furthermore,high-fat diets induced depression-like behaviors in Syrian golden hamsters were conducted to verify the predicted molecular mechanisms acquired from the transcriptome analysis.Results:Transcriptome results revealed that the 24 differentially expressed genes(DEGs)in chronic mild stress(CMS)rats could be reversed after two weeks of KP treatment.The mechanisms of KP in treating depression firstly involved the regulation of several pathology modules,including lipid metabolism,synapse function and inflammation.KP could regulate imbalances of lipid homeostasis in high-fat diet induced depressive symptoms.Furthermore,it was validated that cholesterol metabolism dysfunction can be ameliorated by KP,which was correlated with upregulation of the AdipoR1-BDNF(brainderived neurotrophic factor)co-regulatory pathway.Conclusion:Taken together,our results demonstrated that KP not only alleviates depression via traditional mental illness targets,but it may also simulates the cholesterol metabolism and adiponectin signaling with multi-target characteristics.展开更多
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.
文摘The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.
文摘Cholesterol, being the starting point of steroid hormone synthesis, is a long known modulator of both female and male reproductive physiology especially at the level of the gonads and the impact cholesterol has on gametogenesis. Less is known about the effects cholesterol homeostasis may have on postgonadic reproductive functions. Lately, several data have been reported showing how imbalanced cholesterol levels may particularly affect the post-testicular events of sperm maturation that lead to fully fertile male gametes. This review will focus on that aspect and essentially centers on how cholesterol is important for the physiology of the mammalian epididymis and spermatozoa.
文摘胆固醇稳态对细胞功能和机体健康至关重要,胆固醇调节元件结合蛋白2(sterol-regulatory element binding protein 2,SREBP2)是维持胆固醇稳态的关键调控因子,是一种位于细胞内质网的胆固醇敏感调节器。SREBP2的表达和功能主要受三个水平的调控:(1)SREBF2基因的转录调控,(2)SREBP2蛋白的转运与剪切调控,(3)nSREBP2的修饰及功能调控。该文系统地对上述三个阶段调控的研究进展及其在代谢性疾病中的作用进行了综述,这将为靶向SREBP2研究胆固醇代谢及其代谢异常相关疾病的治疗提供理论参考。
基金supported by grants from the National Institute of Dental and Craniofacial Research, NIH (DE024759, DE026208, DE026509, and DE026767), to J.I.UTHealth School of Dentistry faculty funds to J.I.
文摘Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.
基金supported by National Natural Science Foundation of China(No.81573876 and 81973502)。
文摘Objective:To clarify the anti-depressive potential mechanisms of Kaixin Powder(KP),a drug that helps to prevent and treat depression and other mentaldiseases,from genome-wide transcriptome profiling.Methods:Transcriptome and KEGG pathway analysis were conducted on the hippocampus of depressed rats,then the differentially expressed genes were validated and serum concentration of lipid parameters were identified by enzymatic assays.Furthermore,high-fat diets induced depression-like behaviors in Syrian golden hamsters were conducted to verify the predicted molecular mechanisms acquired from the transcriptome analysis.Results:Transcriptome results revealed that the 24 differentially expressed genes(DEGs)in chronic mild stress(CMS)rats could be reversed after two weeks of KP treatment.The mechanisms of KP in treating depression firstly involved the regulation of several pathology modules,including lipid metabolism,synapse function and inflammation.KP could regulate imbalances of lipid homeostasis in high-fat diet induced depressive symptoms.Furthermore,it was validated that cholesterol metabolism dysfunction can be ameliorated by KP,which was correlated with upregulation of the AdipoR1-BDNF(brainderived neurotrophic factor)co-regulatory pathway.Conclusion:Taken together,our results demonstrated that KP not only alleviates depression via traditional mental illness targets,but it may also simulates the cholesterol metabolism and adiponectin signaling with multi-target characteristics.
