更新于：2024-11-01

CD36

更新于：2024-11-01

基本信息

别名

CD36、CD36 antigen (collagen type I receptor, thrombospondin receptor)、CD36 molecule

+ [16]

简介

Multifunctional glycoprotein that acts as receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21610069). Mechanistically, binding of fatty acids activates downstream kinase LYN, which phosphorylates the palmitoyltransferase ZDHHC5 and inactivates it, resulting in the subsequent depalmitoylation of CD36 and caveolar endocytosis (PubMed:32958780). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellular calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thrombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). Involved in inducing apoptosis in podocytes in response to elevated free fatty acids, acting together with THBS1 (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211). (Microbial infection) Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and the internalization of particles independently of TLR signaling.

关联

项与 CD36 相关的药物

Salvianolic Acid B

丹酚酸B

靶点

CD36

作用机制

CD36 inhibitors

在研机构

南京虹桥医药技术研究所有限公司 [+2]

原研机构-

在研适应症

心绞痛 [+1]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

JC63.1

靶点

CD36

作用机制

CD36 inhibitors

在研机构

McGill University

原研机构

McGill University

在研适应症

角膜新生血管

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

HCW9107(HCW Biologics)

靶点

CD36

作用机制

CD36 inhibitors

在研机构

HCW Biologics Inc.

原研机构

HCW Biologics Inc.

在研适应症

炎症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 CD36 相关的临床试验

CTR20192236 / Completed临床1期

注射用丹酚酸B在中国健康成人受试者的单次与多次用药安全性及耐受性的I期临床研究

1. 主要目的：评价注射用丹酚酸B单次与多次用于中国健康成人受试者的安全性及耐受性。 2. 次要目的，探索注射用丹酚酸B： (1)皮肤试验方法。 (2)单次与多次用于中国健康成人受试者的药代动力学特征。 (3)单次与多次用于中国健康成人受试者的药效学特征。 (4)单次用于中国健康成人受试者的经肾排泄特征。

开始日期2019-11-12

申办/合作机构

南京虹桥医药技术研究所有限公司

[+1]

NCT00113334 / Completed临床1/2期IIT

A Phase 1b/2 Study of ABT-510 (Thrombospondin Analogue) in Patients With Advanced Head and Neck Cancer

The goals of this clinical research study are to see how individuals with advanced head and neck cancer respond to treatment with the new drug thrombospondin (ABT-510) and to learn how effective it is in destroying cancer cells. The safety of ABT-510 and the effect ABT-510 has on cells in the body will also be studied.

开始日期2005-04-01

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

NCT00602199 / Completed临床2期IIT

A Phase II Study of Anti-angiogenesis Therapy for Metastatic Melanoma Using ABT-510

RATIONALE: ABT-510 may stop the growth of melanoma by blocking blood flow to the tumor.
PURPOSE: This phase II trial is studying how well giving ABT-510 works in treating patients with metastatic melanoma.

开始日期2004-11-01

申办/合作机构

Mayo Clinic

[+1]

100 项与 CD36 相关的临床结果

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100 项与 CD36 相关的转化医学

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0 项与 CD36 相关的专利（医药）

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7,724

项与 CD36 相关的文献（医药）

2025-01-01·Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology

Comparative analysis of Scarb1 and Cd36 in grass carp (Ctenopharyngodon idellus): Implications for DHA uptake

Article

The polyunsaturated fatty acid docosahexaenoic acid (DHA) significantly influences fish growth and lipid metabolism. Nevertheless, the specific mechanism by which DHA is transported and exerts its effects remains unclear. Scavenger receptor class B type I (SCARB1) is essential for maintaining cellular cholesterol levels and regulating the immune system in mammals, as well as facilitating the uptake of fatty acids (FAs). Another class B scavenger receptor, cluster-determinant 36 (CD36), is involved in promoting the uptake and transport of long-chain fatty acids. However, the molecular characteristics of the grass carp scarb1 gene have not yet been reported, and the potential role of Scarb1 and Cd36 in mediating DHA transport and metabolism remains uncertain. This study aimed to investigate the effects of Scarb1 and Cd36 on DHA transport. Initially, grass carp scarb1-1 and scarb1-2 were cloned. Predictions were made regarding their structural characteristics, including number and presence of transmembrane domains and glycosylation sites. Furthermore, gene structure analysis revealed that scarb1-1 has two additional exons in the 3'-region compared to scarb1-2. The multiple sequence alignment indicated that Scarb1 exhibits conserved motifs and amino acid residues across vertebrates. mRNA expression of scarb1-1 was the highest in the intestine, while scarb1-2 was highest expressed in adipose tissue, with both having lower expression levels in muscle tissue. Scarb1-1 was primarily localized on the cell membrane, whereas Scarb1-2 was found in both the cell membrane and cytoplasm. After overexpression of grass carp Scarb1-1, Scarb1-2, and Cd36 in HEK 293 T cells, DHA incubation showed that only Cd36 significantly increased cellular DHA relative content, suggesting a potential role of Cd36 in DHA transport. These findings will serve as a basis for further research on fatty acid transport in fish.

2025-01-01·Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Investigation of adipocyte differentiation based on proteomics and intact N-glycopeptide modificationomics

Article

作者: Guan, Yaqun ; Nuermaimaiti, Nurbie ; Zhang, Xiaozheng ; Ma, Wenting ; Abudukeremu, Aikedaimu ; Meng, Xuanyu ; He, Yihuai ; Li, Xin-Yu ; Chen, Xuelei ; Sun, Jiaxin ; Li, Shangkun

OBJECTIVETo investigate the role of N-glycosylation modification of proteins in adipocyte differentiation during the adipogenic process.METHODSSVF cells and adipocytes were analyzed for proteomics and intact N-glycopeptide modificationomics.Differential expression of proteins, glycoforms, and sites between the two groups was screened and subjected to Gene Ontology (GO) functional enrichment analysis, KEGG pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. The top 20 most significantly differentially expressed adipogenic differentiation-related proteins were identified, and the most pronouncedly altered proteins were analyzed for glycoforms, glycan chains, and sites.RESULTSProteomics analysis identified 39,392 peptides and 5208 proteins, while intact N-glycopeptide modification profiling identified 3293 intact glycopeptides, 426 proteins, and 161 glycan chains. Proteomics identified 2510 differentially expressed proteins, with CD36 (Cluster of Differentiation 36, CD36) significantly upregulated. In adipocytes, CD36 had 4 N-glycosylation sites: N79, N220, N320, N417, with N320 being a newly identified site. GO enrichment results indicated that CD36 is associated with fatty acid oxidation, lipid oxidation, and fatty acid uptake into cells.CONCLUSIONMultiple proteins undergo N-glycosylation modification during adipocyte differentiation, with CD36, a fatty acid translocase, being significantly expressed in adipocytes. This suggests that N-glycosylation modification of CD36 may play a crucial role in adipocyte differentiation, providing a foundation for further investigation into the function of CD36 N-glycosylation in adipocyte differentiation.

2024-12-31·Redox Report

Skeletal muscle cystathionine γ-lyase deficiency promotes obesity and insulin resistance and results in hyperglycemia and skeletal muscle injury upon HFD in mice

Article

作者: Xu, Miaomiao ; Lu, Jianqiang ; Lu, Jiani ; Ni, Xin ; Tang, Zhengshan ; Wang, Changnan ; Wang, Fengmei ; Yu, Bo

OBJECTIVESThe objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (Cth^Δskm) mice.METHODSThe Cth^Δskm mice and littermate Cth-floxed (Cth^f/f) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle.RESULTSMetabolomics coupled with transcriptome showed that Cth^Δskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth^f/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. Cth^Δskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cth^f/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in Cth^Δskm+HFD mice. Omics analysis showed differential pathways enriched between Cth^Δskm mice and Cth^f/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in Cth^Δskm+HFD mice compared to Cth^f/f+HFD mice.DISCUSSIONOur results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.

项与 CD36 相关的新闻（医药）

2024-10-21

·生物制药小编

5条肿瘤代谢通路

即使在氧充分的条件下（有氧糖酵解/Warburg效应），癌细胞上调葡萄糖的糖酵解途径形成乳酸，这个过程被认为是恶性肿瘤的标志。代谢活跃的癌细胞导致营养消耗、缺氧、酸性、有毒的代谢物富集的肿瘤微环境，抑制免疫系统。肿瘤细胞代谢与肿瘤微环境（Nat Rev Cancer . 2020 Sep;20(9):516-531）本文简介肿瘤细胞代谢调节的5条信号通路。其他代谢相关文章，请点击下面链接阅读 23种代谢产物与肿瘤免疫 T细胞代谢与功能的关系 1. Hippo Pathway Hippo通路控制细胞增殖、器官大小和组织稳态。它由MAPK家族、MST1/2、LATS1/2以及转录共激活因子YAP和TAZ组成。当该通路被激活时，上游信号磷酸化并激活MST1/2和LATS1/2，从而磷酸化YAP/TAZ。因此，YAP/TAZ通过14-3-3蛋白被隔离在细胞质中，并被E3连接酶β-TRCP降解。 Annu Rev Pathol. 2021 January 24; 16: 299–322 然而，当Hippo信号通路关闭时，YAP/TAZ易位到细胞核，与转录增强相关域(TEAD)转录因子结合，诱导致癌靶基因的表达。 Hippo通路受到广泛的上游调控因子的调控，包括细胞-细胞接触、来自周围环境刺激、Wnt信号传导、GPCR-配体相互作用和各种细胞应激条件。 YAP/TAZ促进糖酵解和谷氨酸代谢 YAP/TAZ活性在许多类型的癌症中都是过度活跃。hHippo通路作为细胞生长的主调节因子，参与了多种代谢过程。YAP/TAZ活性通过直接和间接提高糖酵解酶活性来促进糖酵解。特别是，YAP/TAZ的活性增加了TEAD对GLUT3的表达，并通过FOXC2诱导了HK2的表达。YAP/TAZ还通过Hedgehog信号通路促进LncRNABCAR4的表达，上调HK2和PFKFB3。YAP/TAZ增强谷氨酰胺代谢，增加乳腺癌细胞中谷氨酰胺转运体SLC1A5和SLC7A5的表达。YAP/TAZ和TEAD通过表达氨基酸转运体上调谷氨酰胺和氨基酸代谢。YAP/TAZ诱导谷氨酰胺酶和转氨酶的表达，包括GOT1和PSAT1，它们产生NEAAs和TCA循环中间体。YAP/TAZ积累脂质，直接调节胆汁酸成分，从而增强癌细胞的转移潜能。葡萄糖增强YAP/TAZ的活性细胞周期进程和细胞增殖由营养物质浓度决定。葡萄糖代谢对YAP/TAZ活性有显著影响。高糖水平增加了HSP的葡萄糖通量，产生用于糖基化的UDP-GlcNAc。因此，丰富的葡萄糖诱导YAP O-GlcNAcylation，干扰LATS和βTrCP的相互作用，进而增强YAP/TAZ的活性。在胰腺癌和肝癌中，YAP被O-GlcNAcylation过度激活。 LATS2的糖基化通过干扰乳腺癌中LATS2和MOB1的相互作用来抑制其活性。相反，葡萄糖剥夺诱导的能量应激通过hippo依赖和非依赖的机制抑制YAP/TAZ活性。能量传感器AMPK随着ATP的减少而被激活。AMPK直接磷酸化YAP的丝氨酸61和丝氨酸94，从而阻断YAP-TEAD的相互作用。AMPK通过AMOTL1磷酸化和激活间接抑制YAP。外部激素水平可以调节Hippo通路。脂质激素，如溶血磷脂酸和鞘氨醇-1-磷酸，通过GPCRs抑制该通路，肽激素胰高血糖素增加血糖水平，通过cAMP和PKA激活Hippo通路。脂肪增强YAP/TAZ的活性亚细胞脂质成分也可以调节Hippo通路激酶。SREBP是Hippo通路的上游调控因子。当SREBP被激活时，甲羟戊酸途径增强了RhoAGTPase的香叶酰化。RhoA是一个f-actin的细胞骨架调节因子，而f-actin是一个成熟的LATS激酶的上游因子。因此，癌细胞中脂肪酸代谢的增加会异常激活RhoA，并通过抑制LATS来增强YAP/TAZ的活性。有趣的是，YAP/TAZ在血液系统恶性肿瘤中几乎不表达，而YAP的强制表达已被证明可以介导肿瘤抑制功能。 2. PI3K-AKT/mTOR Pathway 在正常细胞中，细胞的增殖和合成代谢受到外部生长因子（如胰岛素和激素）的微妙调节，PI3K-AKT-mTOR通路是其中一条重要通路。 PI3K/AKT信号通路调节代谢酶。在被胰岛素激活后，AKT通过磷酸化GSK3来抑制糖原合成途径。PI3K/AKT通过代谢酶的翻译后修饰（如磷酸化、糖基化）直接或间接上调糖酵解。例如，AKT磷酸化并激活AS160蛋白，从而增强了GLUT的膜运输。AKT通过抑制磷酸化直接抑制TXNIP，通过抑制内吞作用增加GLUT1/4的膜表达。 AKT还提高了糖酵解酶的效率。AKT通过增加HK2的线粒体整合来磷酸化并激活HK2。AKT使PFKFB磷酸化；这种变化催化果糖-6-磷酸到F-2,6-BP，从而提高糖酵解。AKT信号通路也通过HIF-1α转录因子促进糖酵解。HIF-1激活一些糖酵解组分，包括GLUT。HIF-1诱导LDH促进乳酸分泌和有氧糖酵解。 PI3K/AKT信号通路上调谷氨酰胺和脂肪酸代谢。AKT通过mTORC1增加Myc的翻译，并通过GSK3和FOXO3A抑制Myc的降解。由于MYC调节谷氨酰胺代谢，MYC的激活增加了细胞氮的供应。因此，AKT促进了核苷酸的合成。癌细胞需要从头脂质合成来维持和供应持续的无限细胞分裂所需的膜成分。AKT通过直接磷酸化脂质合成的第一个酶ACLY，影响脂质的新生生物合成过程，从而提高酶的效率。AKT通过ACLY调控增加各种癌症类型中的组蛋白乙酰化 AKT诱导的mTORC1激活增强了SREBP家族的翻译和切割加工。AKT介导的GSK3抑制进一步阻止了SREBP1的降解。因此，了解通过PI3K/AKT信号通路的代谢重编程将阐明PI3K抑制剂对癌症治疗的有效治疗替代方案。 3. Myc Pathway 转录因子c-Myc通过MAX调控基因表达，是癌细胞中最过度活跃的基因之一，位于生长相关信号通路(如EGFR、AKT和GPCRs)的交叉点。 Myc调节与葡萄糖、谷氨酰胺和脂肪酸代谢相关的基因的表达。Myc通过上调糖酵解和谷氨酰胺水解来增强癌细胞的代谢重。Myc诱导许多糖酵解酶(如GLUT、HK2和PFK)，它们催化糖酵解过程相应步骤。 MYC癌基因的激活驱动谷氨酰胺的优先代谢向TCA循环添补反应（Anaplerosis）和随后的氧化磷酸化。MYC癌基因表达的缺失增加了线粒体代谢对葡萄糖的依赖。 4. p53 Pathway P53是最著名的肿瘤抑制基因之一，它影响细胞过程，包括凋亡、细胞周期进程和代谢。p53在细胞应激条件下被激活，如DNA损伤和营养剥夺。根据应激源的类型和强度，它决定了是发生适应还是细胞死亡。p53在转录、翻译和翻译后水平上被调节。p53的稳定性受E3连接酶MDM2的调控。 AMPK磷酸化，乙酰化，从而在能量应激条件下稳定p53。通过上调MDM2来促进p53的降解，p53诱导一个负反馈回路来维持稳态。 p53调节代谢（Cancers 2021, 13, 133） P53减少有氧糖酵解，上调线粒体分解代谢过程，包括脂肪酸氧化(FAO)和OXPHOS；p53转录抑制GLUT1和GLUT4的表达，抑制葡萄糖摄取；抑制TCA循环；增加脂肪酸氧化；增加氧化磷酸化（OXPHOS），积累NADH和FADH2。 5. LKB1/AMPK Pathway AMPK是一种保守性良好的能量传感激酶。AMPK抑制合成代谢途径（脂肪酸合成、mTOR途径），促进分解代谢（糖酵解、Krebs循环、磷酸戊糖途径、脂肪酸氧化和自噬）的细胞过程。因此，AMPK的激活允许细胞承受细胞能量应激条件。与其他代谢蛋白不同，AMPK的调控依赖于AMP和ADP的细胞浓度，但独立于其他代谢中间体。AMP/ATP比值的增加导致AMP相互作用，随后是AMPK的构象变化。在癌症的背景下，应激环境下的AMPK激活，包括缺氧和能量或营养剥夺，赋予了各种癌症的应激抵抗特性。 *红色箭头（激活上调）（Oxid Med Cell Longev . 2019 Oct 31;2019:8730816.） AMPK是一种致癌蛋白还是肿瘤抑制蛋白仍有待确定。在临床环境中，AMPK激活剂，包括2型糖尿病药物二甲双胍和AICAR，被用于抑制癌细胞增殖；然而，AMPK也通过促进原蛋白抗性、迁移和转移作为致癌蛋白。 ACC是AMPK的一个成熟的靶点。ACC在脂肪酸从头合成过程中，ACC介导乙酰辅酶A转化为丙二酰辅酶A。AMPK通过抑制ACC磷酸化来减少ATP的消耗。AMPK降低的脂肪酸合成通量降低了NADPH的消耗。为了满足细胞对脂质代谢物的需求，AMPK通过CD36和其他脂质转运体上调脂肪酸的摄取来维持脂质稳态。蛋白质翻译是高度耗能的，并使用多种合成代谢途径，包括PPP和谷氨酰胺水解。AMPK通过抑制mTORC1和翻译机制，允许癌细胞适应恶劣的营养条件，如葡萄糖剥夺。主要参考文献 Jordan H. Driskill et al，The Hippo Pathway in Liver Homeostasis and Pathophysiology. Annu Rev Pathol. 2021 January 24; 16: 299–322 Robert D. Leone and Jonathan D. Powell, Metabolism of immune cells in cancer, Nat Rev Cancer . 2020 Sep;20(9):516-531 Tambay, V.; Raymond, V.-A.; Bilodeau, M. MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype. Cancers 2021, 13, 4484 : Lahalle, A.; Lacroix, M.; De Blasio, C.; Cissé, M.Y.; Linares, L.K.; Le Cam, L. The p53 Pathway and Metabolism: The Tree That Hides the Forest. Cancers 2021, 13, 133 Francesco Ciccarese et al. LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective,Oxid Med Cell Longev . 2019 Oct 31;2019:8730816.

临床结果

2024-10-13

·生物谷

蔗糖竟能抑制肝癌？Sci Rep | 蔗糖在一定条件下能够减轻DEN诱导的肝纤维化和肿瘤形成，并改善肝脏脂质代谢

过去十年间，肝细胞癌（HCC）的发病率和死亡率显著上升，预计到2040年，新增病例将增加55%，死亡率也将上升56.4%。尽管治疗方法有所进展，但晚期诊断和高复发率依然是主要挑战。HCC的主要风险因素包括乙型和丙型肝炎病毒感染、酒精摄入以及由肥胖引发的非酒精性脂肪性肝炎（NASH）。近年来，蔗糖和高果糖玉米糖浆的过量摄入导致肥胖和代谢相关脂肪性肝病（MAFLD）增加，MAFLD与HCC密切相关，但蔗糖在HCC发生中的具体机制尚不清楚。近日，墨西哥国家基因组医学研究所Julio Isael Pérez-Carreón研究团队在Sci Rep发表了题为Intriguing hepatoprotective effects of sucrose on hepatocellular carcinoma pathogenesis的研究论文，揭示了蔗糖摄入对肝癌模型中肝脏的保护效果。研究表明，蔗糖通过调节脂质代谢和氧化应激反应，改善了肝脏结构，减轻了纤维化和肿瘤形成，同时降低了肝癌标志物的表达，抑制了细胞增殖。这一研究为蔗糖在肝癌中的潜在作用提供了新的见解。本研究主要通过在大鼠模型中使用二乙基亚硝胺（DEN）诱导肝癌，并联合蔗糖，探讨其对HCC发展的潜在影响。实验结果显示，蔗糖和DEN联合使用的大鼠在18周后体重有所恢复，胰腺重量增加，而单独使用DEN的大鼠则表现出显著的体重下降和器官重量减少。组织学分析显示，DEN处理组的肝脏结构严重受损，表现出明显的纤维化和肿瘤形成。然而，联合使用蔗糖的组别显示出较轻的纤维化和更为正常的肝脏结构，表明蔗糖在一定程度上改善了DEN诱导的肝脏损伤。图1. 食用蔗糖可减少实验性HCC中的组织学改变、纤维化、肝硬化和肝酶水平研究结果 1. 蔗糖改善肝脏结构蔗糖摄入组的肝脏脂质代谢有所恢复，尤其是在结节和非结节区域，肝脏中脂肪的积累与对照组相似，这表明蔗糖能够缓解DEN引发的脂质代谢紊乱。在肝功能和脂质代谢方面，虽然ALT水平在DEN组显著升高，但在蔗糖处理组中得到了部分缓解，AST水平在各组间无明显差异。血清脂肪酸和甘油三酯的分析显示，与单独使用DEN的大鼠相比，蔗糖摄入组的脂质水平显著增加，提示蔗糖在减轻DEN诱导的脂质代谢紊乱方面发挥了作用。图2. 蔗糖消耗可减轻甘油三酯和血清游离脂肪酸的减少，在肿瘤前和肿瘤HCC阶段恢复肝实质中的中性脂质 2. 蔗糖降低肝癌标志物的表达基因表达和肿瘤标志物的分析进一步支持了这一观点。蔗糖摄入组中与肝癌相关的标志物Gstp1和Ggt1的表达显著低于DEN组，同时，免疫荧光结果表明蔗糖摄入显著降低了Ki-67阳性细胞的数量，表明肝细胞增殖活动减少。 3. 蔗糖抑制氧化应激反应蔗糖还通过下调KEAP1和NRF2基因的表达，抑制了氧化应激反应，这可能是其发挥肝脏保护作用的机制之一。在脂质代谢相关基因的分析中，蔗糖摄入显著增加了脂肪酸结合蛋白（Fabp1）的表达，同时减少了CD36和Caveolin-1（Cav1）的表达，这表明蔗糖对脂质代谢的调控有积极作用，特别是在脂质运输和氧化应激的调节上。此外，CD36蛋白的免疫荧光分析显示，蔗糖摄入显著抑制了CD36在肝脏中的表达。图3. 在实验性HCC中，食用蔗糖可减少肿瘤发展并减少Ki-67增殖标志物图4. 蔗糖对实验性HCC中KEAP1和NRF2的影响综上所述，该研究发现蔗糖在一定条件下能够减轻DEN诱导的肝纤维化和肿瘤形成，并改善肝脏脂质代谢，表明蔗糖通过调控脂质代谢和氧化应激反应，对肝细胞癌的发展具有潜在的保护作用。这一发现挑战了传统上对高糖饮食与癌症发展之间的负面关联，为未来关于糖类摄入与肝癌之间关系的研究提供了新的视角。参考文献： Aguirre-Maldonado I, Herrera-López EE, López-Zenteno F, et al. Intriguing hepatoprotective effects of sucrose on hepatocellular carcinoma pathogenesis. Sci Rep. 2024;14(1):23689. Published 2024 Oct 10. doi:10.1038/s41598-024-74991-4 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

临床研究

2024-10-11

·生物探索

Cell Metab丨初波/孙金鹏/于晓/柴人杰/徐云飞揭示GPR56感知17α-羟基孕烯醇酮调控铁死亡诱发的肝损伤

引言 G蛋白偶联受体（GPCRs）是人类基因组中最大的膜蛋白家族，介导80%以上细胞跨膜信号转导，大约是34% 临床药物的直接靶标。在脊椎动物中，GPCR超家族根据序列和结构相似性被划分为五个家族。粘附类GPCRs（aGPCRs）作为GPCRs的第二大家族，在调节细胞功能和介导许多生理过程中发挥着关键作用，因此深入了解 GPCR 调节铁死亡的机制将有助于开发新的临床疗法来治疗相关疾病。铁死亡是一种新型的铁依赖的脂质过氧化驱动的程序性细胞死亡方式，它与缺血再灌注损伤（IRI）、阿霉素诱导的组织损伤、神经退行性疾病、癌症免疫治疗和肿瘤抑制等疾病有关【1】。机制上，铁死亡主要受到谷胱甘肽过氧化物酶 4（GPX4 ）- 原型谷胱甘肽（GSH）、铁死亡抑制蛋白 1（FSP1） - 泛醇（CoQH2）、二氢乳清酸脱氢酶（DHODH） - CoQH2和GTP 环水解酶 1（GCH1） - 四氢生物蝶呤（BH4）等四个抗氧化系统的调控，将有毒的脂质过氧化物转化为无毒的脂醇，从而抑制铁死亡的发生。然而，到目前为止，所有已知的基因都是通过非跨膜受体依赖的方式参与铁死亡【2】。GPCRs作为细胞外感知和细胞间通讯的核心调控者，是否通过调控铁死亡发挥功能尚不清楚。同时越来越多的研究表明代谢物在介导铁死亡相关疾病中起重要作用。类固醇激素作为体内重要的一类调节分子，在介导细胞凋亡或坏死中已有报道【3,4】，但关于类固醇激素在调节铁死亡中的作用知之甚少。山东大学孙金鹏教授团队和于晓教授团队合作聚焦于粘附类GPCR的配体鉴定、信号转导和生理功能研究，发现了识别类固醇激素的GPCR亚家族。例如，糖皮质激素的膜受体GPR97、孕酮的膜受体GPR126和DHEA的膜受体GPR64等，发现了粘附类受体家族是识别类固醇激素膜受体的受体亚家族，相关研究自2021年以来连续分别发表在Nature、Nature Chemical Biology、PNAS杂志【5-7】，重塑了多年来人们对类固醇激素作用机制的认知。 2024年10月9日，山东大学基础医学院初波教授研究团队，联合孙金鹏教授团队，于晓教授团队，以及东南大学的柴人杰教授和山东大学齐鲁医院徐云飞教授团队，共同在Cell Metabolism杂志上在线发表了他们最新的研究成果 Sensing steroid hormone 17a-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury。研究团队鉴定了类固醇激素17a-hydroxypregnenolone 的膜受体GPR56与铁死亡密切相关，该研究首次揭示了17-OH PREG-GPR56-CD36 轴介导的脂质代谢是一种新的抗铁死亡途径，其介导的信号转导是维持肝脏稳态的必要条件，为临床肝脏损伤中的治疗方法的开发和应用提供了新的药物研究靶点和治疗策略。该研究团队首先通过体内实验在阿霉素（DOX）诱导的小鼠肝损伤模型中，筛选粘附GPCRs表达变化，发现GPR56显著上调。进一步体外实验通过 GPCR cDNA 文库的筛选，寻找影响细胞铁死亡可塑性的受体，发现 GPR56/ADGRG1 的确改变了铁死亡的可塑性，GPR56的过表达可以有效地保护细胞免受铁死亡的损害。同时，GPR56的缺失改变了多种细胞对铁死亡的敏感性，并加剧DOX或缺血再灌注（IR）诱导的肝损伤。进一步机制研究发现，GPR56通过促进CD36的内吞 - 溶酶体降解的途径，从而降低了含有游离多不饱和脂肪酸（PUFA）的磷脂的丰度，从而有效地抑制铁死亡。为了寻找GPR56的有效激动剂，该研究团队进行了一系列类固醇代谢物的筛选，发现补充17α-羟基孕烯醇酮（17-OH PREG）可以显著增强细胞对铁死亡的抵抗力，并以GPR56依赖的方式保护细胞免受铁死亡。由于大多数类型的临床组织损伤很难提前服用药物以避免组织损伤的发生。在这里，该研究团队的发现揭示了17-OH PREG在损伤后显著减轻了急性和慢性肝损伤。从临床角度来看，该研究发现，通过治疗性给予17-OH PREG治疗肝病可能有效地帮助预防急性和慢性肝衰竭。模式图（Credit: Cell Metabolism）综上所述，该研究团队阐明了类固醇代谢物17-OH PREG通过GPR56/ADGRG1途径抵抗铁死亡的新分子机制，并首次揭示了GPCR和相应的信号传导调控的铁死亡在临床治疗中的潜在重要作用。研究结果为肝脏损伤的潜在治疗提供了新的见解，深度剖析了GPCR受体与铁死亡之间的紧密联系，为临床铁死亡相关疾病的治疗方法的开发和应用提供了新的研究策略。参考文献 1. Stockwell, B.R., Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell, 2022. 185(14): p. 2401-2421. 2. Zhang, H.L., et al., PKCbetaII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol, 2022. 24(1): p. 88-98. 3. King, L.B., et al., A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. Immunity, 1995. 3(5): p. 647-56. 4. Wang, X., et al., Ursolic acid ameliorates hepatic fibrosis in the rat by specific induction of apoptosis in hepatic stellate cells. J Hepatol, 2011. 55(2): p. 379-87. 5. Ping, Y.Q., et al., Structures of the glucocorticoid-bound adhesion receptor GPR97-G(o) complex. Nature, 2021. 589(7843): p. 620-626. 6. Lin, H., et al., Structures of the ADGRG2-G(s) complex in apo and ligand-bound forms. Nat Chem Biol, 2022. 18(11): p. 1196-1203. 7. An, W., et al., Progesterone activates GPR126 to promote breast cancer development via the Gi pathway. Proc Natl Acad Sci U S A, 2022. 119(15): p. e2117004119. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cmet.2024.09.007 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床研究