Identification prognostic features related to sphingolipid metabolism and experimental validation of TRIM47 in hepatocellular carcinoma

Background:The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma(HCC)remains unclear.This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis,immune response,and drug sensitivity.Methods:Data were obtained from The Cancer Genome Atlas(TCGA)-Hepatocellular Carcinoma(LIHC)and Gene Expression Omnibus(GEO,GSE14520 datasets).47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes(KEGG)database.After classifying HCC samples using the Non-negative Matrix Factorization(NMF)clustering method,differentially expressed genes were screened.Then,8 risk genes were obtained by univariate analysis,survival random forest reduction and lasso analysis.The expression of 8 risk genes was verified in vitro.Results:8 risk genes were used to construct the Sphingolipid score model.High-Sphingolipid score predicted poor prognosis of HCC patients.Sphingolipid score was associated with immune checkpoints(IL-1B,TLR4,TGFB1,and IL-10),immune cells(Th2,Treg,MDSC,Neutrophil,Fibroblasts and macrophage),and MAPK Cascade.In the High-Sphingolipid score group,a significantly higher proportion of patients with TP53(p53)mutations was significantly higher(56%).Furthermore,patients with a high-Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs.In vitro validation showed that compared with normal liver cells LX-2,TRIM47,and S100A9 significantly increased in liver cancer cells Hep G2,MHCC-97H,and Hep3B2.1-7,while SLC1A7,LPCAT1,and CFHR4 significantly decreased.Silencing TRIM47 reduced the proliferation and promoted apoptosis.The levels of ceramide synthesis-related indexes(CERS1,CERS6,CERS5,and SPTLC2)increased,and the ACER3 related to catalytic hydrolysis decreased.Conclusion:We constructed a sphingolipid metabolism-related prognostic signature(Sphingolipid score)based on 8 risk genes.TRIM47 may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis.

Characterization of the sphingolipid profiling of Emiliania huxleyi against virus infection

Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.

Structural Determination of Three Sphingolipids from Two Marine-derived Mangrove Endophytic Fungal Strains

A set of three sphingolipids, N-2′-hydroxyplmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingadiene （A）, N-2′-hydroxyl-3′E-octadecenoyl-1-O-β-D-glucopyranosyl-9-methyl-4E, 8E-sphingediene （B） and N-palmitoyldihydrosphingosine （C）, were isolated from two marine-derived mangrove endophytic fungal strains （strains No. 1924 and 3893） from the South China Sea. Their structures were elucidated by 2D NMR and FABMS methods. It is the first time that these sphingolipids were separated and obtained from marine-derived mangrove endophytic fungus from the South China Sea.

Obesity-associated steatotic liver exhibits aberrant or altered sphingolipid composition and preferentially accumulates ceramide species containing long chain fatty acids

The sphingolipid (SL) signaling pathways are induced by reactive oxygen species and proin-flammatory molecules, which are shown to be upregulated in the obese state. The present work was conducted to determine if an altered SL pathway exists, and contributes to the pathogenesis of hepatic steatosis associated with obesity. Steatotic and non-steatotic livers were procured from Zucker Obese female rats and their lean counterparts in this pre-clinical study, and assessed for enzymes involved in degradation as well as in phos-phorylation of proapoptotic SLs. The expression of enzymes [sphingo-myelinase (SMase), ceramidase, and sphingosine kinase-1 (SK1)] and apoptotic proteins (Bax and Bcl-2) was quantified by ELISA and by Western Blot. Sphingomyelin (SM), ceramide, ceramide-1 phosphate (C1P), sphingosine (SPH), and sphingosine-1-phosphate (S1P) levels were quantified by high-performance liquid chroma-tography (HPLC)-tandem mass spectroscopy (MS). Obese steatotic livers exhibited significantly upregulated ceramidase and down-regulated SK1 and C1P levels (P < 0.05), as well as significantly lower levels of SM and higher levels of ceramide species containing long chain fatty acids, compared to their lean counterparts. These findings demonstrate that obese liver harbours SLs that favour a proapoptotic environment. Moreover, accumulation of ceramides containing long chain fatty acids could be involved in the pathogenesis of hepatic steatosis.

Sphingolipids in cardiovascular and cerebrovascular systems:Pathological implications and potential therapeutic targets

The sphingolipid metabolites ceramide,sphingosine,and sphingosine-1-phosphate(S1P) and its enzyme sphingosine kinase(SphK) play an important role in the regulation of cell proliferation,survival,inflammation,and cell death.Ceramide and sphingosine usually inhibit proliferation and promote apoptosis,while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis.Because these metabolites are interconvertible,it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate.The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations.A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat,as it not only produces the pro-growth,anti-apoptotic messenger S1P,but also decreases levels of pro-apoptotic ceramide and sphingosine.Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease,and these observations have considerable relevance for future potential therapeutic targets.

Role of sphingosine kinase localization in sphingolipid signaling

The sphingosine kinases, SK1 and SK2, produce the potent signaling lipid sphingosine-1-phosphate (S1P). These enzymes have garnered increasing interest for their roles in tumorigenesis, inflammation, vascular diseases, and immunity, as well as other functions. The sphingosine kinases are considered signaling enzymes by producing S1P, and their activity is acutely regulated by a variety of agonists. However, these enzymes are also key players in the control of sphingolipid metabolism. A variety of sphingolipids, such as sphingosine and the ceramides, are potent signaling molecules in their own right. The role of sphingosine kinases in regulating sphingolipid metabolism is potentially a critical aspect of their signaling function. A central aspect of signaling lipids is that their hydrophobic nature constrains them to membranes. Most enzymes of sphingolipid metabolism, including the enzymes that degrade S1P, are membrane enzymes. Therefore the localization of the sphingosine kinases and S1P is likely to be important in S1P signaling. Sphingosine kinase localization affects sphingolipid signaling in several ways. Translocation of SK1 to theplasma membrane promotes extracellular secretion of S1P. SK1 and SK2 localization to specific sites appears to direct S1P to intracellular protein effectors. SK localization also determines the access of these enzymes to their substrates. This may be an important mechanism for the regulation of ceramide biosynthesis by diverting dihydrosphingosine, a precursor in the ceramide biosynthetic pathway, from the de novo production of ceramide.

Bile acids and sphingolipids in cholangiocarcinoma

Objective:Cholangiocarcinoma(CCA)is a rare but highly malignant hepatobiliary cancer with a very poor prognosis and limited treatment options.CCA is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids(CBAs),which are correlated with bile duct obstruction.

Sphingolipid metabolism affects the anticancer effect of cisplatin

Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes.Ceramide(Cer),which is the central molecule of this network,has been established to induce apoptosis.However,another molecule,sphingosine-1-phosphate(S1P),exerts the opposite function,i.e.,serves as a regulator of pro-survival.Other sphingolipid molecules,including dihydroceramide,ceramide-1-phosphate,glucosylceramide(Glu Cer),and sphingosine(Sph),or sphingolipid catalytic enzymes such as Sph kinase(Sph K),Cer synthase(Cer S),and S1 P lyase,have also attracted considerable attention,particularly Cer,Glu Cer,Sph K,Cer S,and S1 P lyase,which have been implicated in cisplatin resistance.This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin,particularly in relation to induction of apoptosis and drug resistance.

Emerging roles and therapeutic potentials of sphingolipids in pathophysiology:emphasis on fatty acyl heterogeneity

Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases.Moreover,blood sphingolipids can also be used as biomarkers for disease diagnosis.This review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains.The possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also discussed.Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.

α1-COP modulates plasmodesmata function through sphingolipid enzyme regulation

Callose,aβ-1,3-glucan plant cell wall polymer,regulates symplasmic channel size at plasmodesmata(PD)and plays a crucial role in a variety of plant processes.However,elucidating the molecular mechanism of PD callose homeostasis is limited.We screened and identified an Arabidopsis mutant plant with excessive callose deposition at PD and found that the mutated gene wasα1-COP,a member of the coat protein I(COPI)coatomer complex.We report that loss of function ofα1-COP elevates the callose accumulation at PD by affecting subcellular protein localization of callose degradation enzyme Pd BG2.This process is linked to the functions of ERH1,an inositol phosphoryl ceramide synthase,and glucosylceramide synthase through physical interactions with theα1-COP protein.Additionally,the loss of function ofα1-COP alters the subcellular localization of ERH1 and GCS proteins,resulting in a reduction of Glc Cers and Glc HCers molecules,which are key sphingolipid(SL)species for lipid raft formation.Our findings suggest thatα1-COP protein,together with SL modifiers controlling lipid raft compositions,regulates the subcellular localization of GPI-anchored PDBG2 proteins,and hence the callose turnover at PD and symplasmic movement of biomolecules.Our findings provide the first key clue to link the COPI-mediated intracellular trafficking pathway to the callose-mediated intercellular signaling pathway through PD.

Sphingolipid inhibitor response gene GhMYB86 controls fiber elongation by regulating microtubule arrangement

Although the cell membrane and cytoskeleton play essential roles in cellular morphogenesis,the interaction between the membrane and cytoskeleton is poorly understood.Cotton fibers are extremely elongated single cells,which makes them an ideal model for studying cell development.Here,we used the sphingolipid biosynthesis inhibitor,fumonisin B1(FB1),and found that it effectively suppressed the myeloblastosis(MYB)transcription factor GhMYB86,thereby negatively affecting fiber elongation.A direct target of GhMYB86 is GhTUB7,which encodes the tubulin protein,the major component of the microtubule cytoskeleton.Interestingly,both the overexpression of GhMYB86 and GhTUB7 caused an ectopic microtubule arrangement at the fiber tips,and then leading to shortened fibers.Moreover,we found that GhMBE2 interacted with GhMYB86 and that FB1 and reactive oxygen species induced its transport into the nucleus,thereby enhancing the promotion of GhTUB7 by GhMYB86.Overall,we established a GhMBE2-GhMYB86-GhTUB7 regulation module for fiber elongation and revealed that membrane sphingolipids affect fiber elongation by altering microtubule arrangement.

Phosphorylation of the LCB1 subunit of Arabidopsis serine palmitoyltransferase stimulates its activity and modulates sphingolipid biosynthesis

Sphingolipids are the structural components of membrane lipid bilayers and act as signaling molecules in many cellular processes.Serine palmitoyltransferase(SPT)is the first committed and rate-limiting enzyme in the de novo sphingolipids biosynthetic pathway.The core SPT enzyme is a heterodimer consisting of LONG-CHAIN BASE1(LCB1)and LCB2 subunits.SPT activity is inhibited by orosomucoid proteins and stimulated by small subunits of SPT(ssSPTs).However,whether LCB1 is modified and how such modification might regulate SPT activity have to date been unclear.Here,we show that activation of MITOGEN-ACTIVATED PROTEIN KINASE 3(MPK3)and MPK6 by upstream MKK9 and treatment with Flg22(a pathogen-associated molecular pattern)increases SPT activity and induces the accumulation of sphingosine long-chain base t18:0 in Arabidopsis thaliana,with activated MPK3and MPK6 phosphorylating AtLCB1.Phosphorylation of AtLCB1 strengthened its binding with AtLCB2b,promoted its binding with ssSPTs,and stimulated the formation of higher order oligomeric and active SPT complexes.Our findings therefore suggest a novel regulatory mechanism for SPT activity.

基于“肺通调水道”理论探究CFTR介导下鞘脂代谢失衡对慢性阻塞性肺疾病的调控机制

目的探讨CFTR调控下鞘脂代谢在COPD中的发病过程及作用途径,进一步阐释肺通调水道理论。方法烟熏法建立COPD小鼠模型,同时烟熏加CFTR激动剂建立CFTR模型,观察肺组织病理变化评估小鼠模型,采用LC-MS质谱检测模型血浆中鞘脂代谢产物Ceramide及sphingosine-1-phosphate表达,采用Western blot方法检测小鼠模型肺组织中Sphks、ASM、CFTR蛋白磷酸化水平,采用荧光定量PCR小鼠模型肺组织中Sphks、Smpd基因(ASM)、CFTRmRNA转录水平。结果COPD组、CFTR干预组中S1p表达均较对照组降低(P<0.05),CFTR干预组较COPD组表达高(P<0.05);CFTR、Sphk1蛋白磷酸化水平在COPD组及CFTR干预组均呈低表达,COPD组表达最低与对照组、CFTR干预组有差异(P<0.05),Sphk2在COPD组与对照组存在差异(P<0.05)。ASM在COPD组、CFTR干预组高于对照组(P<0.05)。CFTR mRNA在COPD组及CFTR干预组均较对照组低,COPD组与对照组存在差异(P<0.05),Sphk1 mRNA在对照组表达最高,且与COPD组、CFTR干预组均存在差异(P<0.05),SMPD1 mRNA在COPD组及CFTR干预组呈高表达,且与对照组有差异(P<0.05)。结论探讨肺通调水道功能失司在COPD疾病中的物质变化基础,揭示CFTR通过参与调控鞘脂代谢,从而影响COPD水液代谢的途径。

Emerging Roles of Sphingolipid Signaling in Plant Response to Biotic and Abiotic Stresses

Plant sphingolipids are not only structural components of the plasma membrane and other endomembrane systems but also act as signaling molecules during biotic and abiotic stresses.However,the roles of sphingolipids in plant signal transduction in response to environmental cues are yet to be investigated in detail. In this review,we discuss the signaling roles of sphingolipid metabolites with a focus on plant sphingolipids.We also mention some microbial sphingolipids that initiate signals during their interaction with plants, because of the limited literatures on their plant analogs.The equilibrium of nonphosphorylated and phosphorylated sphingolipid species determine the destiny of plant cells,whereas molecular connections among the enzymes responsible for this equilibrium in a coordinated signaling network are poorly understood.A mechanistic link between the phytohormone-sphingolipid interplay has also not yet been fully understood and many key participants involved in this complex interaction operating under stress conditions await to be identified.Future research is needed to fill these gaps and to better understand the signal pathways of plant sphingolipids and their interplay with other signals in response to environmental stresses.

Leech Poecilobdella manillensis protein extract ameliorated hyperuricemia by restoring gut microbiota dysregulation and affecting serum metabolites

BACKGROUND Hyperuricemia(HUA)is a public health concern that needs to be solved urgently.The lyophilized powder of Poecilobdella manillensis has been shown to significantly alleviate HUA;however,its underlying metabolic regulation remains unclear.AIM To explore the underlying mechanisms of Poecilobdella manillensis in HUA based on modulation of the gut microbiota and host metabolism.METHODS A mouse model of rapid HUA was established using a high-purine diet and potassium oxonate injections.The mice received oral drugs or saline.Additionally,16S rRNA sequencing and ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics were performed to identify changes in the microbiome and host metabolome,respectively.The levels of uric acid transporters and epithelial tight junction proteins in the renal and intestinal tissues were analyzed using an enzyme-linked immunosorbent assay.RESULTS The protein extract of Poecilobdella manillensis lyophilized powder(49 mg/kg)showed an enhanced anti-trioxypurine ability than that of allopurinol(5 mg/kg)(P<0.05).A total of nine bacterial genera were identified to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder,which included the genera of Prevotella,Delftia,Dialister,Akkermansia,Lactococcus,Escherichia_Shigella,Enterococcus,and Bacteroides.Furthermore,22 metabolites in the serum were found to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder,which correlated to the Kyoto Encyclopedia of Genes and Genomes pathways of cysteine and methionine metabolism,sphingolipid metabolism,galactose metabolism,and phenylalanine,tyrosine,and tryptophan biosynthesis.Correlation analysis found that changes in the gut microbiota were significantly related to these metabolites.CONCLUSION The proteins in Poecilobdella manillensis powder were effective for HUA.Mechanistically,they are associated with improvements in gut microbiota dysbiosis and the regulation of sphingolipid and galactose metabolism.

miRNA对褐飞虱鞘脂质代谢基因表达的影响及沉默NlSPT1和Nl SMase4的small RNA分析

【背景】鞘脂质是第二大类膜脂,作为信号转导物质参与细胞生长发育、繁殖及凋亡等过程。鞘脂质代谢酶调控鞘脂质代谢以维持生物体内代谢的稳态。【目的】以重要水稻害虫褐飞虱(Nilaparvata lugens)为研究对象,通过RNA干扰(RNA interference,RNAi)技术检测微小RNA(microRNA,miRNA)生物合成通路核心组分NlAgo1、NlDicer1和NlDrosha沉默后褐飞虱鞘脂质代谢通路相关基因的相对转录水平,结合small RNA测序分析沉默丝氨酸棕榈酰转移酶1(serine palmitoyltransferase 1,SPT1)和鞘磷脂酶4(sphingomyelinase 4,SMase4)基因的差异miRNA,探究miRNA在褐飞虱鞘脂质代谢中的作用,为害虫防治提供新的分子靶标。【方法】利用RNAi技术,分别对羽化后第1天(1 PAE,post adult eclosion)的雌成虫NlAgo1、NlDicer1和NlDrosha进行dsRNA注射,以ds GFP为对照;分别解剖羽化后第5天的卵巢组织,以β-actin作为内参基因,采用实时荧光定量PCR(qRT-PCR)方法检测NlAgo1、NlDicer1和NlDrosha沉默后鞘脂质代谢通路相关基因的表达量变化;根据已有的小RNA文库联合miRNA-靶基因预测软件对可能调控NlSPT1和NlSMase4表达的miRNA进行预测;通过small RNA测序技术对沉默NlSPT1和NlSMase4的差异miRNA进行鉴定和靶基因富集性分析。【结果】与对照组相比,沉默NlAgo1、NlDicer1或NlDrosha显著上调卵巢中NlSPT1和NlSMase4等鞘脂质代谢通路相关基因的表达;靶基因预测结果显示,有6条miRNA能与NlSPT1结合,13条miRNA能与NlSMase4结合;沉默NlSPT1和NlSMase4的差异miRNA的靶基因显著富集在细胞核和蛋白质结合等生物学过程以及内吞作用、内质网加工、MAPK信号通路、TOR信号通路、凋亡、脂质代谢等代谢通路。【结论】NlAgo1、NlDicer1和NlDrosha依赖性的miRNA通过影响鞘脂质代谢相关基因的表达影响鞘脂质代谢。NlSPT1和NlSMase4沉默引起褐飞虱卵巢miRNA表达水平的改变。研究结果可为基于鞘脂质代谢基因为靶标的害虫防治提供理论依据。

代谢组学联合网络药理学分析香蜂草苷缓解非酒精性脂肪肝大鼠的作用机制

目的:利用非靶向代谢组学联合网络药理学研究香蜂草苷改善非酒精性脂肪性肝病(NAFLD)脂代谢的作用机制。方法:将大鼠随机分为正常组、模型组和香蜂草苷组。模型组与香蜂草苷组给予高脂饮食(HFD)8周诱导NAFLD动物模型。灌胃给药,连续8周。采用苏木精—伊红(HE)、油红染色观察细胞形态和脂质堆积情况。用高分辨液相色谱—质谱(UPLCQTOF/MS)对大鼠肝组织进行代谢组学检测,并利用KEGG数据库分析代谢通路。采用网络药理学对香蜂草苷与NAFLD共同作用的靶点进行预测,并联合代谢组学进一步分析潜在的靶点。结果:香蜂草苷明显减轻大鼠肝损伤、抑制肝脏脂质的过度沉积;正交偏最小二乘判别分析(OPLS-DA)分析显示组间的代谢物有显著差异,火山图显示正常组与模型组存在404个差异代谢物(上调293个,下调111个),模型组与香蜂草苷组存在147个差异代谢物(上调95个,下调52个);代谢通路分析显示差异代谢物主要富集于鞘脂代谢通路;网络药理学筛选药物与疾病共同靶点共139个,联合代谢组学和网络药理学分析显示,香蜂草苷可通过调节TNF、Bcl2、Mapk8、Pik3ca、Akt1、mTOR、Gsk3β来调控鞘脂代谢通路和胰岛素抵抗。结论:香蜂草苷能够通过鞘脂代谢通路和胰岛素抵抗调节脂质代谢紊乱从而发挥治疗NAFLD的作用。

Changes of sphingolipids profiles after ischemia-reperfusion injury in the rat liver

Background Hepatic ischemia-reperfusion （I/R） injury occurs in many clinical procedures. The molecular mechanisms responsible for hepatic I/R injury however remain unknown. Sphingolipids, in particular ceramide, play a role in stress and death receptor-induced hepatocellular death, contributing to the progression of several liver diseases including liver I/R injury. In order to further define the role of sphingolipids in hepatic I/R, systemic analysis of sphingolipids after reperfusion is necessary. Methods We investigated the lipidomic changes of sphingolipids in a rat model of warm hepatic I/R injury, by delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry （DE MALDI-TOF-MS）. Results The total amounts of ceramide and sphingomyelin and the intensity of most kinds of sphingolipids, mainly sphingomyelin, significantly increased at 1 hour after reperfusion （P 〈0.05） and reached peaks at 6 hours after reperfusion （P 〈0.01） compared to controls. Six new forms of ceramide and sphingomyelins appeared 6 hours after reperfusion, they were （m/z） 537.8, 555.7, 567.7, 583.8, 683.5 and 731.4 respectively. A ceramide-monohexoside （m/z） 804.4 （CMH（d18：1C22：1＋Na）＋） also increased after reperfusion and correlated with extent of liver injury after reperfursion. Conclusions Three main forms of sphingolipids, ceramide, sphingomyelin and ceramide-monohexoside, are related to hepatic I/R injury and provide a new perspective in understanding the mechanisms responsible for hepatic I/R injury.

不同脂质成分影响认知障碍的研究进展

认知障碍是目前主要公共卫生挑战之一,其发病机制尚不明确。目前针对认知障碍尚未发现有效的治疗及干预措施,大部分研究表明通过干预血管危险因素可预防或减缓认知衰退,其中脂质组学成为研究热点。脂质是人体的重要组成部分,其成分可通过不同途径影响认知功能。因此,本文就脂质中常见成分对认知功能的影响做一综述。

Bile acids and sphingolipids in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.