脑硫脂

脑硫脂（英语：sulfatide，硫酸脑苷脂、硫苷脂、硫脂类、半乳糖酰基鞘氨醇/3-O-sulfogalactosylceramide、SM4、硫酸化半乳糖/sulfated galactocerebroside）属于一类，具体上是"硫酸糖脂"（sulfoglycolipid）的一类，因其含硫酸基糖脂。脑硫脂的合成主要在内质网开始而在高尔基体结束，过程中神经酰胺转化成半乳糖之后硫化为脑硫脂。在髓磷脂的半乳糖脂中，有1/5是脑硫脂。脑硫脂主要被发现在由中枢神经系统的少突胶质细胞及周围神经系统中，施旺细胞所产生髓鞘细胞膜的胞膜外片上。然而，脑硫脂也存在于真核生物组织的许多细胞之细胞膜的胞膜外片上。
因为脑硫脂是一种多功能分子，它可以在多种生物学领域中使用。除了作为膜成分，脑硫脂功能作用在（靶向蛋白）、、神经可塑性、记忆及"神经胶质细胞轴突的相互作用"（glial-axon interaction）等功能上。脑硫脂也作用在一些生理过程及系统上，包括神经系统、免疫系统、胰岛素分泌、凝血、病毒性疾病，及细菌感染等。其结果是，脑硫脂或可关联于或也能够结合到肾组织、癌症细胞/组织、红血球细胞及血小板的表面、免疫系统中的CD1a-d细胞、许多细菌细胞、一些病毒、髓鞘、神经元，以及星形胶质细胞等组织上。
硫脂显出异常的代谢或改变也与各种病理病症有关包括在神经病理学（neuropathology）上，比如异染性脑白质退化症(MLD)、阿兹海默病及帕金森氏症。脑硫脂也与糖尿病，癌远端转移，及病毒包括HIV-1（HIV-1/Subtypes of HIV）、甲型流感病毒、丙型肝炎以及牛痘病毒（Vaccinia virus）等有关。此外，硫脂的过度显现出与癫痫及「听原性癫痫发作」（audiogenic seizures）以及其它神经系统里的病理状态有关。
过往及正在进行的研究将继续阐明脑硫脂的多种生物学功能及其众多的影响，且在病理学上已相关联到脑硫脂。大多数研究利用小鼠模型，而且异源性表达（heterologous expression）系统也被利用，包括到但不限于"Madin-Darby犬肾细胞"及羰基硫-7细胞。
脑硫脂历史.
脑硫脂是第一个从人脑中分离出来的"磺胺糖脂"(sulfoglycolipid)。 Originally, in 1933, it was first reported by Blix that sulfatide contained amide bound fatty acid and 4-sphingenine and that the sulfate of sulfatide was thought to be attached to the C6 position of galactose.-->于1955年再次得到"桑豪社"(Thannhauser)和"施密特"(Schmidt)支持；然而，通过气相色谱法，"山口山村"(Tamio Yamakawa)发现硫酸盐实际上附著在半乳糖的C3位置，而不是C6位置。于是，1962年，山川(Yamakawa)完成了纠正后的硫苷化合物的。
硫脂合成与降解.
脑硫脂合成开始于尿苷二磷酸半乳糖(UDP-半乳糖)与2-羟基化、或非羟基化神经酰胺之间的反应。 Here, GalCer reacts with 3’-phosphoadenosine-5’-phosphosulfate (PAPS) to make sulfatide. This reaction is catalyzed by cerebroside sulfotransferase (CST). CST is a homodimeric protein that is found in the Golgi apparatus. It has been demonstrated that mice models lacking CST, CGT, or both are incapable of producing sulfatide indicating that CST and CGT are necessary components of sulfatide synthesis. 
磺酰胺类降解发生在溶酶体中。这里，芳基硫酸酯酶A水解硫酸盐基团。然而，为了使该反应进能够进行，比如鞘糖蛋白B必须存在。 Arylsulfatase A can then hydrolyze the sulfate group. Accumulation of sulfatide can cause Metachromatic Leukodystrophy, a lysosomal storage disease and may be caused because of a defect in arylsulfatase A, leading to an inability to degrade sulfatide.
硫脂的生物学功能.
脑硫脂也被证明在肾脏中起了次要的作用。
神经系统.
脑硫脂是神经系统中的主要成分，并且在周围神经系统以及中枢神经系统中的髓鞘中发现含有高水平的脑硫脂。 When lacking sulfatide, myelin sheath is still produced around the axons; however, when lacking sulfatide the lateral loops and part of the nodes of Ranvier are disorganized, so the myelin sheath does not function properly. -->因此，缺乏脑硫脂可导致肌肉无力、颤抖及共济失调。
鉴别髓鞘.
如上所述，脑硫脂主要在神经系统中的少突神经胶质细胞及施旺细胞里被发现。 However, research suggests that sulfatide has a greater role than simply being a structural component of the membrane. This is because sulfatide is upregulated, i.e.there is an increase in sulfatide, prior to the myelin sheath being wrapped around the axon, and experiments in cerebroside sulfotransferase (CST) deficient mice have shown that sulfatide operates as a negative regulator (inhibitor) of oligodendrocyte differentiation. Accordingly, further research has demonstrated that when sulfatide is deficient, there is a two to threefold increase in oligodendrocyte differentiation, evidence providing support that sulfatide operates as a negative regulator or inhibitor of oligodendrocyte differentiation. Myelination also appears to be stimulated by sulfatide in the Schwann Cells. Such stimulation is thought to occur through the following interactions. First, sulfatide binds to tenascin-R or laminin in the extracellular matrix, which goes on to bind signaling molecules such as F3 and integrins in the glial membrane. This causes signaling through c-src/fyn kinase. Specifically, the laminin α6β1-integrin forms a complex with fyn kinase and focal adhesion kinase that enables signaling, which, in turn, causes myelination to begin. Sulfatide binding to laminin also causes c-src/fyn kinase activation and initiation of basement membrane formation.
硫苷脂和髓鞘及淋巴细胞蛋白.
脑硫脂也与髓鞘及淋巴细胞蛋白(MAL)有关。 MAL is also believed to form membrane microdomains (small regions on the membrane with distinct structure and function) in which lipids, such as sulfatide, are stabilized into lipid rafts, allowing stabilization of the glial-axon junctions.
神经胶质细胞轴突连接及信号.
脑硫脂对周围神经系统的神经胶质轴突也是很重要的一种成分。 In order to form a paranodal junction, Caspr and contactin form a complex with neurofascin 155. It has been shown that sulfatide may be involved in the recruitment and formation of neurofascin 155 in lipid rafts; neurofascin 155 protein clusters then bring Caspr and contactin into the membrane to form the complex, which allows the formation of stable glial-axon junctions. Consequently, sulfatide plays an important role in maintaining the paranodal glial-axon junctions, which allows for proper glial-axon interaction and signaling. Sulfatide has also been shown to be an inhibitor of myelin associated axon outgrowth, and small amounts of sulfatide have been found in astrocytes and neurons, which is also indicative of its importance in glial-axon junctions.-->
异常脑硫脂显现.
脑硫脂的异常显现与一些神经系统疾病(neurological disorder)有所关联。 High levels of sulfatide in the gray matter in the cerebellum and in the superior frontal lobe have been associated with Parkinson's disease. Additionally, accumulation of sulfatide in neurons causes audiogenic seizures, which have been shown to be lethal in mouse models. On the other hand, reduced levels of sulfatide in the cerebral gray and white matter have been associated with Alzheimer's disease.-->
免疫系统.
不同类型的细胞在其表面上呈现出的抗原包括：
这些不同细胞类型中的每一种细胞在CD1的显现。 CD1a, CD1b, and CD1c subtypes present lipid antigens to T cells, while CD1d cells present lipids, glycolipids, and lipoproteins to Natural Killer T-cells. CD1 a through c cell subtypes initiate T helper type 1 and type 2 responses, and they facilitate sulfatide loading onto the surface of the cells. There are two types of cell subtypes that interact with CD1d cells: Type 1 Natural Killer T- cells and Type 2 Natural Killer T- cells. Type 2 Natural Killer T-cells are able to recognize sulfatide/ CD1d tetramers, and as a result, they are activated by different tissues specific forms of sulfatide. Type 2 Natural Killer T-cells that react with sulfatide help aid in protection from autoimmune disease and ischemic reperfusion. They are capable of such protection because the Type 1 Natural Killer T-cells can be regulated by Type 2 Natural Killer T-cells that react with sulfatide by altering how the dendritic cells function.
Sulfatide also acts as an L-selectin and P-selectin ligand, but it does not act as an E- selectin ligand. Selectins are adhesion molecules that facilitate the capture of circulating leukocytes. Sulfatide is also expressed on the surface of many types of cancer cells and tissues. Accordingly, sulfatide may function as a ligand for P-selectin, which facilitates cancer metastasis. Additionally, when L-selectin and sulfatide bind, upregulation of the chemokine co-receptor’s (CXCR4) expression is observed, specifically on the surfaced of leukocytes.
Sulfatide may also function as a receptor for chemokines, which are small chemostatic cytokines, and they provide directional signals for leukocyte movement.-->趋化因子涉及：
Autoimmunity also affects sulfatide levels. When an enhanced antibody response against myelin lipids occurs, including sulfatide in patients with Multiple Sclerosis, the demyelination process is increased significantly. When sulfatide and gangliosides are present, the proliferation or production of Natural Killer-T cells that produce cytokines are activated. However, when CD1d deficient-mice are tested for their response to sulfatide, the same response is not seen, which indicates that in myelin, sulfatide is a glycolipid that possesses immunodominance.
Locally, the disruption of myelin due to the infiltration of T cells and macrophages, results in the phagocytosis of myelin by microglia or macrophages, suggesting that the T cells are presented with myelin lipids by CD1 molecules at sites of inflammation.-->
止血/血栓.
脑硫脂有凝血因子和抗凝血因子的两种功能。 On the other hand, sulfatide also helps to improve blood coagulation and thrombosis: first, sulfatide is believed to aid in thrombosis through its participation with coagulation factor XII; second, sulfatide binding to annexin V accelerates coagulation; third, sulfatide and P-selectin interactions expressed on platelets, help to ensure stable platelet adhesion and aggregation. However, most of these conclusions have been drawn using exogenous forms of sulfatide. Consequently, additional research and experimentation on endogenous sulfatide is necessary to fully understand the role of sulfatide in coagulation and thrombosis. Sulfatide is also present in serum lipoproteins, which are believed to be associated with the cause and development of cardiovascular disease.-->
肾脏.
脑硫脂也可以在肾脏中发现。 For example, sulfatide is a ligand for L-selectin, which is a receptor that can be found in the kidneys. Specifically, L-selectin is a lymphoid receptor, and the binding between L-selectin and sulfatide in the kidney’s interstitium plays a major role in monocyte permeation and infiltration into the kidney. Additionally, sulfatide is also found in the glandular stomach epithelium and in the apical membranes of the distal kidney tubuli where Myelin and lymphocyte protein(MAL) is expressed. MAL forms complexes with sulfatide and other glycosphingolipids, and these complexes have been shown to play a role in apical sorting and stabilization of sphingoglycolipid enriched areas.-->
病理细胞和组织的作用.
异染性脑白质退化症.
-->
脑硫脂起著髓鞘的重要作用。 This then results in demyelination because of the buildup of sulfatide and is the main cause of Metachromatic Leukodystrophy.
However, how sulfatide buildup causes demyelination and neural degeneration is still mostly unknown. Metachromatic Leukodystrophy results in neurological manifestations that are centered on the impairment of the central nervous system and the peripheral nervous system including the following: seizures, progressive coordination and speech problems, and behavioral disturbances. Treatment is still being studied and evaluated, but mice studies indicate that treatments including gene therapy, cell based therapies using oligodendrocyte progenitors cells, enzyme replacement therapy, or adeno-associated viral and lentiviral mediated gene therapy may prove to be effective in reducing the effects of Metachromatic Leukodystrophy.-->
糖尿病.
Sulfatide may also be involved in not just type I diabetes, but also type II diabetes. Specifically, sulfatide is capable of inhibiting TNF-α secretion. When there are low serum levels of sulfatide, as well as elevated production of TNF-α in patients that have type II diabetes, it is commonly associated with insulin resistance. However, sulfatide may mediate suppression of type II diabetes through the activation of potassium protein channels.-->
癌症和肿瘤.
However, experimentation using renal cancer cell lines has given some insight into the mechanism for the elevated levels of sulfatide expression in cancer cells. Specifically, cerebroside sulfotransferase (CST) is elevated as it passes along a signaling pathway which involves:
This path results in the accumulation of sulfatide in renal cancer cell lines. Additionally, sulfatide can accumulate on the surface of cancer cells. This indicates that sulfatide may serve as a specific ligand for P-selectin. This would contribute to increased metastasis of the cancer. However, more research is needed to elucidate the relationship between the elevated levels of sulfatide expression and the initiation and metastasis mechanisms of cancer, but sulfatide may be a useful serum biomarker for early tumor detection.-->
病毒感染.
HIV-1.
磺胺类药物显示涉及HIV亚型的感染。 These glycoprotein complexes can interact with CD4, a viral receptor molecule, which induces a change in the conformation of gp120. This change in conformation allows the gp120 complex to interact with the chemokine co-receptor and the insertion of the fusion peptide,gp41, into the membrane of the host cell. This allows the HIV-1 virus to enter into the cell. Gp120 can also bind to glycolipids like sulfatide and galactocerebroside (GalCer). Sulfatide binds strongly to the V3 loop of gp120, which does not interact with CD4. Consequently, sulfatide acts as an alternate virus receptor in CD4- cells, and it participates in transmembrane signaling. However, sulfatide has little function in HIV-1 infection of CD4+ cells.
The binding of gp120 to GalCer has the ability to start the fusion of HIV-1, but the binding of gp120 to sulfatide does not. Sulfatide is not a functional receptor. However, experiments have shown that sulfatide and GalCer compete for the ability to bind to gp120, and sulfatide has been shown to have the strongest binding affinity for recombinant gp120 of all the glycolipids tested. Therefore, this suggests that when sulfatide is attached to HIV-1, it cannot interact with the chemokine co-receptor because of the instability of the complex between gp120 and sulfatide, which therefore prevents the initiation of the fusion process. This indicates that sulfatide can prevent HIV-1 infection by mediating gp120 binding, which, in turn, prevents the fusion process; consequently, it has been demonstrated that sulfatide treatments may lead to the inhibition of HIV-1 replication.
Additionally,HIV-1 infected patients often suffer from myelin degeneration in the central nervous system. These patients have elevated levels of sulfatide in the cerebrospinal fluid (CSF) and anti-sulfatide antibodies in the serum. Elevated levels of anti-sulfatide antibodies can cause demyelination. This is caused by the binding of the anti-sulfatide antibodies to the surface of the myelin sheath and/or the surface of Schwann Cells, which then activates a complete cascade of demyelination. Also, advanced stage AIDS patients can develop Guillain-Barré syndrome (GBS). Guillain-Barré syndrome is classified as an acute autoimmune polyneuropathy, which specifically affects the peripheral nervous system of the infected patient. Experimentation has shown that anti-sulfatide autoimmune antibodies may contribute to the development of Guillain-Barré syndrome in AIDS patients as well as the development of peripheral nervous system injury in HIV-1 infected patients.-->
C型肝炎.
与混合型（MC）相关的丙型肝炎病毒（HCV）之几名患者在其血浆中具有升高的抗硫酸酯抗体水平。 It is believed there is a relationship between HCV and MC; however, the exact role of HCV in relation to the cause of MC has not yet been fully understood or discovered. Nevertheless, sphingolipid synthesis in the host, has been demonstrated to be necessary for HCV replication , which indicates that sulfatide may be involved in the replication of HCV.-->
A型流感.
甲型流感病毒（IAV）与脑硫脂强烈地结合。 Sulfatide has also been shown to inhibit influenza A virus sialidase activity. However, this is only under acidic conditions not neutral conditions. To fully understand the role of sulfatide in the cycle of IAV infection, research have expressed sulfatide in Madin-Darby canine kidney cells, which can express sulfatide and support IAV replication and in COS-7 cells, which do not have the ability to express sulfatide and do not support IAV replication sufficiently. Consequently,the COS-7 cells were transfected with galactosyltransferase and cerebroside sulfotransferase genes from the Madin-Darby canine kidney cells and used to make two cell clones with the ability to express sulfatide .
These cells were then infected with the IAV virus, and research has shown that the sulfatide enhanced cells infected with IAV show increased IAV replication in the progeny virus, 500-3,000 times the parent virus. However, the sulfatide enriched cells also have a small reduction in initial infection compared to the parent cells. The opposite is shown in sulfatide knockdown Madin-Darby canine kidney cells, exhibiting a reduction in progeny virus concentration vs. parent virus concentration and an increase in initial infection. Overall, such experiments demonstrate that sulfide rich cells enhance IAV replication and that sulfatide on the cell’s surface may play a role in the replication of IAV.
Further experimentation has demonstrated that sulfatide enriched cells, in which sulfatide binds to hemagglutinin, enhances IAV replication by increasing the progeny virus particle formation; this is done through the promotion of nuclear export of IAV formed viral ribonucleoproteins from the nucleus to the cytoplasm. Experimentation has also demonstrated that if binding is inhibited between sulfatide and hemagglutinin that viral particle formation and replication would be inhibited, again suggesting that the binding between sulfatide and hemagglutinin facilitates IAV replication.-->
牛痘病毒.
与已知导致天花的天花病毒密切相关。 It has been demonstrated in mouse models that sulfatide prevents the attachment of vaccinia virus to the cell’s surface, while also preventing death in mouse models that are typically lethal. This suggests that sulfatide may be one receptor for the vaccinia virus.-->
细菌感染.
脑硫脂结合到许多类的细菌及菌株，包括：
脑硫脂作为糖脂受体，其功能是帮助将这些细菌粘附到黏膜表面。
Helicobacter pylori, enterotoxigenic E. coli TOP10 strain, 987P-fimbriated enterotoxigenic E. coli (a strain of E. coli), and Lactobacillus reuteri are different strains of bacteria that are found to adhere to the gastrointestinal tract’s mucosal surface. Here, sulfatide is present within the tract and is loaded from outside the tract, aiding the bacteria in adherence to the mucosa.
STb is an enterotoxin type B that is heat stable; additionally, it is secreted by the enterotoxigenic E. coli strain, and it causes diarrheal diseases in humans and many other species of animals. STb also binds strongly to sulfatide as demonstrated by its binding to sulfatide present on the mucosal surface of a pig’s jejunum. Additional experimentation suggests that sulfatide is a functional STb receptor.
Sulfatide may also play a role in Mycobacterium tuberculosis, which is the agent that causes tuberculosis in humans. Experimentation suggests that sulfatide may be involved in Mycobacterium tuberculosis infection, and it may be an element of the cell wall of the bacteria Mycobacterium tuberculosis.-->
临床意义.
阿兹海默病的角色.
从阿兹海默病的早期发作阶段开始，脑硫脂的含量在脑组织里就大量的降低。在阿兹海默病的温和阶段，大脑中的脑硫脂损失在白质神经组织部分可高达50％、而在灰质神经组织部分更高达90％。在阿兹海默病患者的脑脊液中之脑硫脂脂浓度也是比较低的。 神经元功能的特性损失伴随著阿兹海默病并经由神经元及突触损失而发生，且损失的是脑硫脂的脂质类。 -->此外，硫脂的损失被观察到只发生在该疾病的一开始，然而在较严重的阶段，却极少发生额外的脑硫脂损失。
脑组织中的脑硫脂经由观察，其中载脂蛋白E(Apolipoprotein E/ApoE)已被研究过，特别是ε4"等位基因"(allele)。载脂蛋白Eε4"等位基因"是唯一已知的遗传风险因子、明显的表现在晚发性的阿兹海默病。 拥有载脂蛋白Eε4"等位基因"(allele)有较高风险底会生成阿尔茨海默氏症。载脂蛋白E为涉及包括胆固醇在内的许多脂质运输的一种蛋白，并而能调节中枢神经系统中能含有多少的脑硫脂，且介导系统的稳态结构。业已发现，较高水平的载脂蛋白E与较大的脑硫脂耗损呈正相关。 载脂蛋白E的相关蛋白从髓磷脂取得脑硫脂，然后降解脑硫脂成各种化合物，例如硫酸盐。当载脂蛋白E增加时，取自髓磷脂的脑硫脂量也增加；因此，有更多的脑硫脂耗损。
脑硫脂还涉入乙型淀粉样蛋白(Amyloid beta)肽的清除。乙型淀粉样蛋白肽是阿兹海默病的标志之一。当它们没有适当的降低，这些肽积聚并产生斑块，这些斑块是乙型淀粉样蛋白肽片的团块，而且和阿兹海默病有相当的关联。乙型淀粉样蛋白肽的清除是很重要的，最好要让这种斑块的积累现象不要出现。经由内吞的途径，脑硫脂可促进乙型淀粉样蛋白肽的去除。因此，当有高含量的脑硫脂时，则就有较低量的乙型淀粉样蛋白肽。因为阿兹海默氏疾病的受试者具有较低脑硫脂水平，故而乙型淀粉样蛋白肽的清除率较低，这使得肽在大脑里积聚并产生斑块。
与维生素K的关系.
维生素K已被发现与脑硫脂有所关联。不仅在动物中，维生素K已经被观察到影响脑里的脑硫脂浓度，而且在细菌里也有类似的现象。神经系统中的维生素K是负责酶的活化、诸如脑硫脂的运作，而且酶对于脑磷脂的生物合成是必需的。当维生素K拮抗剂华法林被添加到动物模型系统中，脑硫脂就受损。 然而，当维生素K被添加回系统中，脑硫脂合成就正常的运作，这表明脑硫脂的合成、维生素K是必要的因素。