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Bile acids and sphingolipids in non-alcoholic fatty liver disease

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Chinese Medical Journal 2022年第10期135卷 1163-1171页

作者： Kaitlyn G.Jackson Grayson W.Way Huiping Zhou Department of Microbiology and Immunology Virginia Commonwealth University School of MedicineRichmondVA 23298USA Center for Clinical and Translational Research Virginia Commonwealth University School of MedicineRichmondVA 23298USA Central Virginia Veterans Healthcare System RichmondVA 23249USA.

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.

关键词： Bile acids sphingolipids Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis

sphingolipids Profiling of Plasma in Patients with Diabetes Mellitus Associated with Atherosclerosis by a Novel Normal-Phase UPLC-QToF MS Method

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Journal of Analysis and Testing 2017年第3期1卷 245-254页

作者： Min Li Li Yang Yining Huang Yu Bai Huwei Liu Beijing Institute for Drug Control(Beijing Center for Health Food and Cosmetics Control) Beijing 102206China Beijing National Laboratory for Molecular Sciences Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of EducationInstitute of Analytical ChemistryCollege of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China Department of Neurology Peking University First HospitalBeijing 100034China

A novel normal-phase UPLC-QToF MS method was developed for sphingolipids analysis,which was then applied to separate and identify seven classes of sphingolipids in plasma.The time-consuming of this novel method was much shorter than previous 2D LC–MS method,while the sensitivity,repeatability and resolution for sphingolipids analysis were better or comparable.Besides,the differences of lipids in human plasma among diabetes mellitus patients,diabetes mellitus associated with atherosclerosis patients and control subjects were also compared.Finally,12 sphingolipids species were identified as the amounts of which in diabetes mellitus associated with atherosclerosis patients were significantly higher than them in diabetes mellitus patients(VIP>1.0,p value1.5).As the isomers of GalCs and GluCs were successfully separated,it was found that five GluCs,rather than GalCs,were included in these 12 potential biomarkers.These results suggest the need to separate GalCs from GluCs,and also indicated that there may be some extra activation pathways of diabetes mellitus associated with atherosclerosis,different from the atherosclerosis pathway and the diabetes mellitus pathway,causing cardiovascular disease.

关键词： UPLC-QToF MS Diabetes mellitus Atherosclerosis sphingolipids Lipidomics Cardiovascular disease

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

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Chinese Medical Journal 2009年第24期122卷 3025-3031页

作者： ZHAI Shu-ting LIU Guang-yi XUE Fei SUN Gong-ping LIANG Liang CHEN Wei XU Guo-dong LI Jun-jian YANG Jun LIANG Ting-bo Department of Hepatobiliary and Pancreatic Surgery Key Laboratory of Combined Multi-organ Transplantation of Ministry of Public Health First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310003 China Department of Toxicology Zhejiang University School of PublicHealth Hangzhou Zhejiang 310031 China

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.

关键词： lipidomic sphingolipids liver ischemia-reperfusion matrix-assisted laser desorption ionizationtime-of-flight mass spectrometry

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

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World Journal of Cardiology 2013年第4期5卷 75-86页

作者： Masahito Kawabori Rachid Kacimi Joel S Karliner Midori A Yenari Department of Neurology San Francisco and San Francisco Veterans Affairs Medical CenterUniversity of CaliforniaSan FranciscoCA 94121United States Department of Cardiology VA Medical CenterUniversity of California San FranciscoSan FranciscoCA 94121United States

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.

关键词： sphingolipids Sphingosine-1-phosphate Sphingosine kinase Ceramide kinase

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

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Journal of Integrative Plant Biology 2023年第6期65卷 1585-1601页

作者： Yuan Li Hanwei Cao Tingting Dong Xiaoke Wang Liang Ma Kun Li Huiqiang Lou Chun-Peng Song Dongtao Ren State Key Laboratory of Plant Environmental Resilience College of Biological SciencesChina Agricultural UniversityBeijing 100193China State Key Laboratory of Agro-Biotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health College of Biological SciencesChina Agricultural UniversityBeijing 100193China Collaborative Innovation Center of Crop Stress Biology Henan Province.Institute of Plant Stress BiologySchool of Life ScienceHenan UniversityKaifeng 475001China

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.

关键词： Arabidopsis MAPK phosphorylation sphingolipids

Deciphering lipid dysregulation in ALS:from mechanisms to translational medicine

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Translational Neurodegeneration 2022年第1期11卷 192-218页

作者： Ira Agrawal Yong Shan Lim Shi-Yan Ng Shuo-Chien Ling Department of Physiology Yong Loo Lin School of MedicineNational University of SingaporeTahir Foundation BuildingMD116-03-H12 Science Drive 2Singapore 117549Singapore Healthy Longevity Translational Research Programme Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore Institute of Molecular and Cell Biology A*STAR Research EntitiesSingaporeSingapore Program in Neuroscience and Behavior Disorders Duke-National University of Singapore Medical SchoolSingaporeSingapore.

Lipids,defined by low solubility in water and high solubility in nonpolar solvents,can be classified into fatty acids,glycerolipids,glycerophospholipids,sphingolipids,and sterols.Lipids not only regulate integrity and fluidity of biologi-cal membranes,but also serve as energy storage and bioactive molecules for signaling.Causal mutations in SPTLC1(serine palmitoyltransferase long chain subunit 1)gene within the lipogenic pathway have been identified in amyo-trophic lateral sclerosis(ALS),a paralytic and fatal motor neuron disease.Furthermore,lipid dysmetabolism within the central nervous system and circulation is associated with ALS.Here,we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis.Among the different lipids,accumulation of ceramides,arachidonic acid,and lysophosphatidylcholine is commonly emerging as detri-mental to motor neurons.We end with exploring the potential ALS therapeutics by reducing these toxic lipids.

关键词： Amyotrophic lateral sclerosis sphingolipids Triglycerides Phospholipids Cholesterol esters Fatty acids Ceramides Arachidonic acid Lysophosphatidylcholine Eicosanoids

Cellular Lipidome Changes during Retinoic Acid(RA)-Induced Differentiation in SH-SY5Y Cells:A Comprehensive In Vitro Model for Assessing Neurotoxicity of Contaminants

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Environment & Health 2023年第2期1卷 110-120页

作者： Michelle Camdzic Diana S.Aga G.Ekin Atilla-Gokcumen Department of Chemistry University at BuffaloThe State University of New York(SUNY)BuffaloNew York 14260United States

The SH-SY5Y,neuroblastoma cell line,is a common in vitro model used to study physiological neuronal function and the neuronal response to different stimuli,including exposure to toxic chemicals.These cells can be differentiated to neuron-like cells by administration of various reagents,including retinoic acid or phorbol12-myristate-13-acetate.Despite their common use,there is an incomplete understanding of the molecular changes that occur during differentiation.Therefore,there is a critical need to fully understand the molecular changes that occur during differentiation to properly study neurotoxicity in response to various environmental exposures.Previous studies have investigated the proteome and transcriptome during differentiation;however,the regulation of the cellular lipidome in this process is unexplored.In this work,we conducted liquid chromatography−mass spectrometry(LC−MS)-based untargeted lipidomics in undifferentiated and differentiated SH-SY5Y cells,induced by retinoic acid.We show that there are global differences between the cellular lipidomes of undifferentiated and differentiated cells.Out of thousands of features detected in positive and negative electrospray ionization modes,44 species were identified that showed significant differences(p-value≤0.05,fold change≥2)in differentiated cells.Identification of these features combined with targeted lipidomics highlighted the accumulation of phospholipids,sterols,and sphingolipids during differentiation while triacylglycerols were depleted.These results provide important insights into lipid-related changes that occur during cellular differentiation of SH-5YSY cells and emphasize the need for the detailed characterization of biochemical differences that occur during differentiation while using this in vitro model for assessing ecological impacts of environmental pollutants.

关键词： lipidomics SH-SY5Y differentiation triacylglycerides phospholipids sphingolipids sterols

Dihydrosphingosine-lnduced Programmed Cell Death in Tobacco BY-2 Cells Is Independent of H2O2 Production

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Molecular Plant 2011年第2期4卷 310-318页

作者： Christophe Lachaud Universite de Toulouse UPS UMR 5546 Surfaces Cellulaires et Signalisation chez les Vegetaux BP 42617 F-31326 Castanet-Tolosan France CNRS UMR 5546 BP 42617 F-31326 Castanet-Tolosan France

Sphinganine or dihydrosphingosine （d18：0, DHS）, one of the most abundant free sphingoid Long Chain Base （LCB） in plants, has been recently shown to induce both cytosolic and nuclear calcium transient increases and a correlated Programmed Cell Death （PCD） in tobacco BY-2 cells. In this study, in order to get deeper insight into the LCB signaling pathway leading to cell death, the putative role of Reactive Oxygen Species （ROS） has been investigated. We show that DHS triggers a rapid dose-dependent production of H2O2 that is blocked by diphenyleniodonium （DPI）, indicating the involvement of NADPH oxidase（s） in the process. In addition, while DPI does not block DHS-induced calcium increases, the ROS production is inhibited by the broad spectrum calcium channel blocker lanthanum （La^3＋）. Therefore, ROS production occurs downstream of DHS-induced Ca^2＋ transients. Interestingly, DHS activates expression of defense-related genes that is inhibited by both La^3＋ and DPI. Since DPI does not prevent DHS-induced cell death, these results strongly indicate that DHS-induced H2O2 production is not implicated in PCD mechanisms but rather would be associated to basal cell defense mechanisms.

关键词： Tobacco BY-2 cells calcium signaling cytosolic calcium aequorin sphingolipids LCBs dihydrosphingosine sphinganine apoptosis Programmed Cell Death （PCD） Reactive Oxygen Species （ROS） H2O2 oxidative burst.

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

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Molecular Plant 2018年第11期11卷 1328-1343页

作者： Usman Ali Hehuan Li Xuemin Wang Liang Guo National Key Laboratory of Crop Genetic Improvement Huazhong Agricultural UniversityWuhan 430070China Department of Biology University of MissouriSt.LouisMO 63121USA Donald Danforth Plant Science Center St.LouisMO 63132USA

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.

关键词： sphingolipids long-chain bases sphingolipid signaling biotic stress abiotic stress