更新于：2024-05-01

CERS6

ceramide synthase 6

更新于：2024-05-01

基本信息

别名

Ceramide synthase 6、CERS6、LAG1 homolog, ceramide synthase 6

+ [4]

简介

Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA) (PubMed:17977534, PubMed:17609214, PubMed:23530041, PubMed:26887952, PubMed:31916624). Can use other acyl donors, but with less efficiency (By similarity). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624). Ceramides generated by CERS6 play a role in inflammatory response (By similarity). Acts as a regulator of metabolism and hepatic lipid accumulation (By similarity). Under high fat diet, palmitoyl- (C16:0-) ceramides generated by CERS6 specifically bind the mitochondrial fission factor MFF, thereby promoting mitochondrial fragmentation and contributing to the development of obesity (By similarity).

关联

100 项与 CERS6 相关的临床结果

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100 项与 CERS6 相关的转化医学

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0 项与 CERS6 相关的专利（医药）

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156

项与 CERS6 相关的文献（医药）

2024-01-26·Psychopharmacology

The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer's disease model mice and its mechanism.

Article

作者: Xin Liu ; Yongzeng Jin ; Xinyi Cheng ; Qinghua Song ; Yanan Wang ; Ling He ; Tong Chen

RATIONALE:

The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline.

OBJECTIVES:

This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD.

RESULTS:

The ICR mice intracerebroventricularly injected with Aβ_1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData.

CONCLUSIONS:

Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain-liver axis.

2023-11-29·Nature communications

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.

Article

作者: Philipp Hammerschmidt ; Sophie M Steculorum ; Cécile L Bandet ; Almudena Del Río-Martín ; Lukas Steuernagel ; Vivien Kohlhaas ; Marvin Feldmann ; Luis Varela ; Adam Majcher ; Marta Quatorze Correia ; Rhena F U Klar ; Corinna A Bauder ; Ecem Kaya ; Marta Porniece ; Nasim Biglari ; Anna Sieben ; Tamas L Horvath ; Thorsten Hornemann ; Susanne Brodesser ; Jens C Brüning

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C_16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

2023-08-08·Diabetes

An Enhancer Within Abcb11 Regulates G6pc2 in C57BL/6 Mouse Pancreatic Islets.

Article

作者: Mark P Keller ; Emily M Hawes ; Kathryn L Schueler ; Donnie S Stapleton ; Kelly A Mitok ; Shane P Simonett ; James K Oeser ; Leesa L Sampson ; Alan D Attie ; Mark A Magnuson ; Richard M O'Brien

G6PC2 is predominantly expressed in pancreatic islet beta cells where it encodes a glucose-6-phosphatase catalytic subunit that modulates the sensitivity of insulin secretion to glucose by opposing the action of glucokinase, thereby regulating fasting blood glucose (FBG). Prior studies have shown that the G6pc2 promoter alone is unable to confer sustained islet-specific gene expression in mice, suggesting the existence of distal enhancers that regulate G6pc2 expression. Using information from both mice and humans, and knowledge that single nucleotide polymorphisms (SNPs) both within and near G6PC2 are associated with variations in FBG in humans, we identified several putative enhancers 3' of G6pc2. One region, herein referred to as enhancer I, resides in the 25th intron of Abcb11 and binds multiple islet-enriched transcription factors. CRISPR-mediated deletion of enhancer I in C57BL/6 mice had selective effects on the expression of genes near the G6pc2 locus: in isolated islets G6pc2 and Spc25 expression were reduced ~50%, and Gm13613 expression was abolished, whereas Cers6 and Nostrin expression were unaffected. This partial reduction in G6pc2 expression enhanced islet insulin secretion at basal glucose concentrations but did not affect FBG or glucose tolerance in vivo, consistent with the absence of a phenotype in G6pc2 heterozygous C57BL/6 mice.

项与 CERS6 相关的新闻（医药）

2023-10-10

·生物探索

FTO在溃疡性结肠炎中起重要作用

肠道上皮细胞(IECs)中RNA N6-甲基腺苷(m6 A)修饰的解除影响肠道免疫细胞并导致肠道炎症。然而，脂肪质量和肥胖相关蛋白(FTO)，m6 A去甲基化酶之一，在溃疡性结肠炎(UC)患者中的功能仍不十分清楚。 2023年9月21日，上海交通大学洪洁、陈豪燕及刘瑞欣共同通讯在Gut（IF=25）在线发表题为“Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis”的研究论文，该研究发现FTO缺乏破坏CerS6介导的鞘脂代谢可加重溃疡性结肠炎。该研究在UC患者的内部队列和外部队列中发现了FTO下调。DSS处理下，Ftoflox/ flox；Villin-cre小鼠肠道菌群失调，促炎巨噬细胞浸润增加，Th17细胞分化增强。 FTO缺乏导致编码神经酰胺合成酶基因CerS6的m6 A修饰增加，mRNA稳定性降低，导致CerS6下调，S1P在IECs中积累。随后，IECs分泌S1P触发促炎巨噬细胞分泌血清淀粉样蛋白A蛋白1/3，最终诱导Th17细胞分化。此外，通过生物信息学分析和实验验证，作者发现FTO表达较低的UC患者可能对vedolizumab治疗有更好的反应。总之，FTO下调通过降低CerS6表达促进UC，导致IECs中S1P积累增加，并通过m6A依赖机制加重结肠炎。UC患者较低的FTO表达可能会增强他们对维多单抗治疗的反应。炎症性肠病(IBD)是指一组原因不明的慢性炎症性疾病，包括溃疡性结肠炎(UC)和克罗恩病(CD)。UC患者患结肠癌的风险更高UC的发展受个体遗传易感性、环境因素和表观遗传调控等多种因素的影响。近年来的研究强调了表观遗传调控在UC发病机制中的重要作用。m6 A是一种广泛分布且丰富的mRNA表观遗传修饰，在热休克反应、细胞分化和RNA代谢等多种生物过程中发挥重要作用。 mRNA的m6 A修饰是由甲基转移酶复合物催化的，该复合物主要由三个转录因子组成：甲基转移酶样3 (METTL3)、METTL14和Wilms ' tumor 1- associated protein (WTAP)。这种修饰被两种去甲基化酶去除：脂肪质量相关和肥胖相关蛋白(FTO)和AlkB同源物5 (ALKBH5)。各种研究表明，m6 A修饰参与UC的发病机制。具体来说，敲除T细胞中的METTL14会导致Treg细胞的失调和自发性结肠炎。此外，Treg细胞中Foxp3介导的METTL3缺失增加了Th1和Th17的应答然而，其他m6 A修饰成员在UC进展中的作用尚不清楚。神经酰胺合成酶6 (CerS6)在肠道和免疫系统中高度表达，是一种优先生成C16 -神经酰胺的酶不同疾病模型的CerS6缺陷小鼠表现出不同的病理形态。一方面，缺乏CerS6会加重小鼠实验性自身免疫性脑脊髓炎(EAE)，另一方面，缺乏CerS6会减少饮食性肥胖模型中巨噬细胞的浸润。鞘脂代谢已被证明在结肠炎中发挥作用，生物活性脂质鞘脂素-1-磷酸(S1P)正成为一种新的治疗靶点。一般来说，S1P水平受两种酶(Sphk1和Sphk2)的活性调控，这两种酶催化鞘氨醇磷酸化，或者通过控制鞘氨醇的量来调节在神经酰胺合成酶家族(CerS1-6)中，有报道称Cers2和Cers6可调节大脑、衰老胃平滑肌细胞和葡聚糖硫酸钠(DSS)诱导的炎性结肠中的鞘氨醇水平。然而，m6 A修饰是否会影响神经酰胺和S1P的平衡尚不清楚。该研究检测了m6 A修饰在UC患者中的参与，并发现了FTO的保护作用，这对UC具有重要的生物学、机制和临床意义。作者研究了FTO介导的m6 A修饰在表观遗传稳定CerS6(一种参与鞘脂代谢的必需酶)中的作用，强调了m6 A外转录组修饰在UC和鞘脂代谢中的关键作用。该研究对UC患者的临床管理具有实际意义，并有可能为临床试验提供新的创新方法。评估FTO表达水平和鞘脂代谢水平对于使用生物制剂和S1PR调节剂有效管理UC患者至关重要。内容来源于网络，如有侵权，请联系删除。

信使RNA

2023-09-12

·Science Daily

Blocking proteins could pull the plug on power for colon tumors

Scientists discovered a previously unknown interaction between proteins that is responsible for supplying energy to tumor cells and could hold significant implications for the development of future treatments for colon cancer. Through study findings published Friday in Cell Reports, a team of scientists at VCU Massey Cancer Center discovered a previously unknown interaction between proteins that is responsible for supplying energy to tumor cells and could hold significant implications for the development of future treatments for colon cancer. "This study is really exciting because we may be able to use these findings to inform the development of an entirely new cancer drug right here at Massey," said study author Can Senkal, Ph.D., a member of the Cancer Biology research program at Massey and an assistant professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine. The potential answer lies within a class of fatty compounds known as ceramides. Ceramides regulate a number of vital cellular functions, and many cancer drugs stimulate ceramide generation to help fend off disease. When that production of ceramide is cut off, cancer cells can survive and grow more efficiently. Senkal and his team began extensively screening cells in the lab to identify what proteins regularly interact with ceramide-producing proteins to identify potential patterns that could warrant further investigation. Ceramide synthases -- the enzymes responsible for the generation of ceramide -- come in a variety pack of six different flavors: Ceramide synthase 1-6. Through their research, Senkal's team observed that the first flavor, ceramide synthase 1 (CerS1), was highly interactive with a particular protein known as heat shock protein 27 (Hsp27). Heat shock proteins act like chaperones for other proteins to retain their full function; however, an overabundance of them can tip the scales and prevent ceramide synthases from doing their job. The researchers also noticed that Hsp27 activity was higher in many colon cancer cells while at the same time CerS1 activity was significantly lower, prompting Senkal and his team to consider if the absence of one was connected to the presence of the other. "There is this yin-yang kind of relationship, which gave us the idea to follow it," Senkal said. "Hsp27 is like the bad guy holding back the good guy, CerS1." Through the study, they identified a specific biological mechanism through which Hsp27 interacted with and inhibited the function of CerS1 in colon cancer cells. By deliberately blocking the activity of Hsp27 in these cells, the researchers confirmed the decreased presence of Hsp27 led to a heightened reactivation of CerS1, which in turn forced a reduction in mitochondrial function. "Cancer cells rely on mitochondria to have the energy to multiply. Without it, the cancer cells can no longer sustain the amount of energy they need and die," Senkal said. By blocking the function of these heat shock proteins, they were essentially able to reactivate the cellular hand that could pull the plug on the power source connected to the cancer, Senkal said. This revelation led the study authors to suggest that Hsp27 could be a primary target in the creation of novel therapies for colon cancer. "We can really go after these protein-protein interactions and precisely reactivate certain enzymes while we don't touch others," Senkal said. These findings are the result of a decade's worth of research by Senkal and his team, in an area which he noted isn't really being explored by anyone else. Senkal knows this won't be an overnight achievement, but hopes to collaborate with other scientists at Massey in a long-term effort to apply these findings to in-house novel drug development at the cancer center. Although this study showed encouraging results in colon cancer, they hope to broaden the scope of this research to additional solid tumors in which the overexpression of Hsp27 has been observed, including lung, pancreatic and prostate cancers. "We hope to demonstrate this connection in other tumors as well, which might better represent the patient population in Massey's catchment area," Senkal said. Massey was recently designated by the National Cancer Institute as a Comprehensive Cancer Center, the highest recognition available that reflects a center's scientific leadership, depth and breadth of research, effective community outreach and cancer research training and education. Collaborators on this study include Rowan Boyd, Sachin Kempelingaiah, Saurav Majumder, Ph.D., Grace Mavodza, Ph.D., Johnny Stiban, Ph.D. and Alexandra Straus of the VCU School of Medicine; and Yusuf Hannun, M.D., Lina Obeid, M.D., and Varun Reddy of Stony Brook University.