Journal of Lipid Research最新文献_第5页

Highly reliable LC-MS lipidomics database for efficient human plasma profiling based on NIST SRM 1950. 基于 NIST SRM 1950 的高度可靠的 LC-MS 脂质组学数据库，可用于高效的人体血浆分析。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-10 DOI: 10.1016/j.jlr.2024.100671

Sara Martínez, Miguel Fernández-García, Sara Londoño-Osorio, Coral Barbas, Ana Gradillas

{"title":"Highly reliable LC-MS lipidomics database for efficient human plasma profiling based on NIST SRM 1950.","authors":"Sara Martínez, Miguel Fernández-García, Sara Londoño-Osorio, Coral Barbas, Ana Gradillas","doi":"10.1016/j.jlr.2024.100671","DOIUrl":"10.1016/j.jlr.2024.100671","url":null,"abstract":"Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS)-based methods have become the gold standard methodology for the comprehensive profiling of the human plasma lipidome. However, both the complexity of lipid chemistry and LC-HRMS-associated data pose challenges to the characterization of this biological matrix. In accordance with the current consensus of quality requirements for LC-HRMS lipidomics data, we aimed to characterize the NIST® Standard Reference Material for Human Plasma (SRM 1950) using an LC-ESI(+/-)-MS method compatible with high-throughput lipidome profiling. We generated a highly curated lipid database with increased coverage, quality, and consistency, including additional quality assurance procedures involving adduct formation, within-method m/z evaluation, retention behavior of species within lipid chain isomers, and expert-driven resolution of isomeric and isobaric interferences. As a proof-of-concept, we showed the utility of our in-house LC-MS lipidomic database -consisting of 592 lipid entries- for the fast, comprehensive, and reliable lipidomic profiling of the human plasma from healthy human volunteers. We are confident that the implementation of this robust resource and methodology will have a significant impact by reducing data redundancy and the current delays and bottlenecks in untargeted plasma lipidomic studies.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100671"},"PeriodicalIF":5.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GCKIII kinases control hepatocellular lipid homeostasis via shared mode of action. GCKIII 激酶通过共同的作用模式控制肝细胞脂质稳态

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-10 DOI: 10.1016/j.jlr.2024.100669

Emmelie Cansby, Mara Caputo, Emma Andersson, Rasool Saghaleyni, Marcus Henricsson, Ying Xia, Bernice Asiedu, Matthias Blüher, L Thomas Svensson, Andrew J Hoy, Margit Mahlapuu

{"title":"GCKIII kinases control hepatocellular lipid homeostasis via shared mode of action.","authors":"Emmelie Cansby, Mara Caputo, Emma Andersson, Rasool Saghaleyni, Marcus Henricsson, Ying Xia, Bernice Asiedu, Matthias Blüher, L Thomas Svensson, Andrew J Hoy, Margit Mahlapuu","doi":"10.1016/j.jlr.2024.100669","DOIUrl":"10.1016/j.jlr.2024.100669","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease has emerged as a leading global cause of chronic liver disease. Our recent translational investigations have shown that the STE20-type kinases comprising the GCKIII subfamily-MST3, STK25, and MST4-associate with hepatic lipid droplets and regulate ectopic fat storage in the liver; however, the mode of action of these proteins remains to be resolved. By comparing different combinations of the silencing of MST3, STK25, and/or MST4 in immortalized human hepatocytes, we found that their single knockdown results in a similar reduction in hepatocellular lipid content and metabolic stress, without any additive or synergistic effects observed when all three kinases are simultaneously depleted. A genome-wide yeast two-hybrid screen of the human hepatocyte library identified several interaction partners contributing to the GCKIII-mediated regulation of liver lipid homeostasis, that is, PDCD10 that protects MST3, STK25, and MST4 from degradation, MAP4K4 that regulates their activity via phosphorylation, and HSD17B11 that controls their action via a conformational change. Finally, using in vitro kinase assays on microfluidic microarrays, we pinpointed various downstream targets that are phosphorylated by the GCKIII kinases, with known functions in lipogenesis, lipolysis, and lipid secretion, as well as glucose uptake, glycolysis, hexosamine synthesis, and ubiquitination. Together, this study demonstrates that the members of the GCKIII kinase subfamily regulate hepatocyte lipid metabolism via common pathways. The results shed new light on the role of MST3, STK25, and MST4, as well as their interactions with PDCD10, MAP4K4, and HSD17B11, in the control of liver lipid homeostasis and metabolic dysfunction-associated steatotic liver disease susceptibility.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100669"},"PeriodicalIF":5.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modeling enzyme competition in Eicosanoid metabolism in macrophage cells using a cybernetic framework. 利用控制论框架模拟巨噬细胞中二十烷类化合物代谢过程中的酶竞争。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-10 DOI: 10.1016/j.jlr.2024.100666

Sana Khanum, Shakti Gupta, Mano R Maurya, Rubesh Raja, Lina Aboulmouna, Shankar Subramaniam, Doraiswami Ramkrishna

{"title":"Modeling enzyme competition in Eicosanoid metabolism in macrophage cells using a cybernetic framework.","authors":"Sana Khanum, Shakti Gupta, Mano R Maurya, Rubesh Raja, Lina Aboulmouna, Shankar Subramaniam, Doraiswami Ramkrishna","doi":"10.1016/j.jlr.2024.100666","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100666","url":null,"abstract":"Cellular metabolism is a complex process involving the consumption and production of metabolites, as well as the regulation of enzyme synthesis and activity. Modeling of metabolic processes is important to understand the underlying mechanisms, with a wide range of applications in metabolic engineering and health sciences. Cybernetic modeling is a powerful technique that accounts for unknown intricate regulatory mechanisms in complex cellular processes. It models regulation as goal-oriented, where the levels and activities of enzymes are modulated by the cybernetic control variables to achieve the cybernetic objective. This study employed cybernetic model to study the enzyme competition between arachidonic acid (AA) and eicosapentaenoic acid (EPA) metabolism in murine macrophages. AA and EPA compete for the shared enzyme cyclooxygenase (COX). Upon external stimuli, AA produces pro-inflammatory 2-series prostaglandins (PGs) and EPA metabolizes to anti-inflammatory 3-series PGs, where pro- and anti- inflammatory responses are necessary for homeostasis. The cybernetic model adequately captured the experimental data for control and EPA-supplemented conditions. The model is validated by performing an F-test, conducting leave-one-out-metabolite cross-validation, and predicting an unseen experimental condition. The cybernetic variables provide insights into the competition between AA and EPA for the COX enzyme. Predictions from our model suggest that the system undergoes a switch from a predominantly pro-inflammatory state in the control to an anti-inflammatory state with EPA-supplementation. The model can also be used to analytically determine the AA and EPA concentrations required for the switch to occur. The quantitative outcomes enhance understanding of pro- and anti-inflammatory metabolism in RAW 264.7 macrophages.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100666"},"PeriodicalIF":5.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

6-O-alkyl 4-methylumbelliferyl-β-D-glucosides as selective substrates for GBA1 in the discovery of glycosylated sterols. 6-O 烷基 4-甲基伞形酮酰基-β-D-葡萄糖苷作为 GBA1 的选择性底物，用于发现糖基化甾醇。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-10 DOI: 10.1016/j.jlr.2024.100670

Stef Bannink, Kateryna O Bila, Joosje van Weperen, Nina A M Ligthart, Maria J Ferraz, Rolf G Boot, Daan van der Vliet, Daphne E C Boer, Herman S Overkleeft, Marta Artola, Johannes M F G Aerts

{"title":"6-O-alkyl 4-methylumbelliferyl-β-D-glucosides as selective substrates for GBA1 in the discovery of glycosylated sterols.","authors":"Stef Bannink, Kateryna O Bila, Joosje van Weperen, Nina A M Ligthart, Maria J Ferraz, Rolf G Boot, Daan van der Vliet, Daphne E C Boer, Herman S Overkleeft, Marta Artola, Johannes M F G Aerts","doi":"10.1016/j.jlr.2024.100670","DOIUrl":"10.1016/j.jlr.2024.100670","url":null,"abstract":"Gaucher disease (GD) is a lysosomal storage disorder (LSD) resulting from inherited glucocerebrosidase (GBA1) deficiency. GD diagnosis relies on GBA1 activity assays, typically employing 4-methylumbelliferyl-β-D-glucopyranoside (4MU-β-Glc) as fluorogenic substrate. However, these assays suffer from background 4MU release by the non-lysosomal GBA2 and cytosolic GBA3 enzymes. Here we developed GBA1-selective fluorogenic substrates by synthesizing a series of 6-O-acyl-4MU-β-Glc substrates with diverse fatty acid tails. Because of the chemical and enzymatic instability of the ester bonds, analogs of 6-O-palmitoyl-4MU-β-Glc (3) with different chemical linkages were synthesized. 6-O-alkyl-4MU-β-Glc 9, featuring an ether linkage, emerged as the most optimal GBA1 substrate, exhibiting both a low Km and compared to substrate 3 a high Vmax. Importantly, substrate 9 is not hydrolyzed by GBA2 and GBA3 and therefore acts as a superior substrate for GD diagnosis. Plants contain glycosyl phytosterols (campesterol, β-sitosterol, and sigmasterol) that may also be acylated at C-6. LC-MS/MS analysis revealed that 6-O-acylated and regular glycosylcholesterol (HexChol) tend to be increased in spleens of patients with GD. Moreover, significant increases in 6-O-acyl-glycosyl-phytosterols were detected in GD spleens. Our findings suggest uptake of (6-O-acyl)-glycosyl-phytosterols from plant food and subsequent lysosomal processing by GBA1, and comprise the first example of accumulation of an exogenous class of glycolipids in GD. Excessive exposure of rodents to glycosylated phytosterols has been reported to induce manifestations of Parkinson's disease (PD). Further investigation is warranted to determine whether (6-O-acyl)-glycosyl-phytosterols could contribute to the enigmatic link between inherited defects in GBA1 and the risk for PD.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100670"},"PeriodicalIF":5.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PCPE2: Expression of multifunctional extracellular glycoprotein associated with diverse cellular functions. PCPE2：多功能细胞外糖蛋白的表达与多种细胞功能有关。

IF 8.3 2区医学

Journal of Lipid Research Pub Date : 2024-10-05 DOI: 10.1016/j.jlr.2024.100664

Michael J Thomas, Hao Xu, Angela Wang, Mirza Ahmar Beg, Mary G Sorci-Thomas

{"title":"PCPE2: Expression of multifunctional extracellular glycoprotein associated with diverse cellular functions.","authors":"Michael J Thomas, Hao Xu, Angela Wang, Mirza Ahmar Beg, Mary G Sorci-Thomas","doi":"10.1016/j.jlr.2024.100664","DOIUrl":"10.1016/j.jlr.2024.100664","url":null,"abstract":"Procollagen C-endopeptidase enhancer 2, known as PCPE2 or PCOC2 (gene name, PCOLCE2) is a glycoprotein that resides in the extracellular matrix, and is similar in domain organization to PCPE1/PCPE, PCOC1 (PCOLCE1/PCOLCE). Due to the many similarities between the two related proteins, PCPE2 has been assumed to have biological functions similar to PCPE. PCPE is a well-established enhancer of procollagen processing activating the enzyme, BMP-1. However, reports show that PCPE2 has a strikingly different tissue expression profile compared to PCPE. With that in mind and given the paucity of published studies on PCPE2, this review examines the current literature citing PCPE2 and its association with specific cell types and signaling pathways. Additionally, this review will present a brief history of PCPE2's discovery, highlighting structural and functional similarities and differences compared to PCPE. Considering the widespread use of RNA sequencing techniques to examine associations between cell-specific gene expression and disease states, we will show that PCPE2 is repeatedly found as a differentially regulated gene (DEG) significantly associated with a number of cellular processes, well beyond the scope of procollagen fibril processing.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100664"},"PeriodicalIF":8.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potential causal and temporal relationship between plasma triglyceride levels and circulating leukocyte. 血浆甘油三酯水平与循环白细胞之间的潜在因果关系和时间关系。

IF 8.3 2区医学

Journal of Lipid Research Pub Date : 2024-10-05 DOI: 10.1016/j.jlr.2024.100662

Jing Xian Fang, Hui Min Zou, Jian Meng, Yu Han, Xue Hu, Qing Gu, Sui Jun Wang, Xing Zhen Liu

{"title":"Potential causal and temporal relationship between plasma triglyceride levels and circulating leukocyte.","authors":"Jing Xian Fang, Hui Min Zou, Jian Meng, Yu Han, Xue Hu, Qing Gu, Sui Jun Wang, Xing Zhen Liu","doi":"10.1016/j.jlr.2024.100662","DOIUrl":"10.1016/j.jlr.2024.100662","url":null,"abstract":"Circulating triglyceride (TG) and leukocytes, the main components of the vascular system, may impact each other and co-fuel atherosclerosis. While the causal relationship between plasma TG levels and leukocyte counts remains unclear. Bidirectional Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationship between TG levels and the counts of leukocytes and their subtypes. A cross-lagged panel model (CLPM) using longitudinal healthy screening data (13,389 adults with a follow-up of 4 years) was fitted to examine the temporal relationship between them. Genetically predicted plasma TG levels were positively associated with total leukocyte counts (TLC) [β(se) = 0.195(0.01)], lymphocyte counts (LC) [β(se) = 0.196(0.019)], and neutrophil counts (NC) [β(se) = 0.086(0.01)], which remained significant after adjusting for several confounders. Inversely, the genetically predicted TLC [β(se) = 0.033(0.008)], LC [β(se) = 0.053(0.008)], and NC [β(se) = 0.034(0.008)] were positively associated with plasma TG levels. However, when all three of them were put into the MR model adjusted for each other, only LC was significantly associated with TG levels. There was no association between genetically predicted TG levels and monocyte counts (MC), basophil counts, and eosinophil counts. The results of CLPM showed that the temporal effect of elevated TLC, MC, LC, and NC on plasma TG levels was stronger than the inverse effect. Our findings suggest causal associations of plasma TG levels with TLC, LC, and NC. In turn, LC was positively associated with plasma TG levels. Additionally, elevated circulating LC may precede high plasma TG levels.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100662"},"PeriodicalIF":8.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A fatty acid-ordered plasma membrane environment is critical for Ebola virus matrix protein assembly and budding. 脂肪酸有序的质膜环境对埃博拉病毒基质蛋白的组装和出芽至关重要。

IF 8.3 2区医学

Journal of Lipid Research Pub Date : 2024-10-05 DOI: 10.1016/j.jlr.2024.100663

Souad Amiar, Kristen A Johnson, Monica L Husby, Andrea Marzi, Robert V Stahelin

引用次数: 0

Fads2 knockout mice reveal that ALA prevention of hepatic steatosis is dependent on delta-6 desaturase activity. Fads2 基因敲除小鼠表明，ALA 对肝脏脂肪变性的预防作用依赖于 delta-6 去饱和酶的活性。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-19 DOI: 10.1016/j.jlr.2024.100642

Blair MacLeod, Chenxuan Wang, Liam H Brown, Emma Borkowski, Manabu T Nakamura, Kyle Rd Wells, Keith R Brunt, Ewa Harasim-Symbor, Adrian Chabowski, David M Mutch

{"title":"Fads2 knockout mice reveal that ALA prevention of hepatic steatosis is dependent on delta-6 desaturase activity.","authors":"Blair MacLeod, Chenxuan Wang, Liam H Brown, Emma Borkowski, Manabu T Nakamura, Kyle Rd Wells, Keith R Brunt, Ewa Harasim-Symbor, Adrian Chabowski, David M Mutch","doi":"10.1016/j.jlr.2024.100642","DOIUrl":"10.1016/j.jlr.2024.100642","url":null,"abstract":"The production of the omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from alpha-linolenic acid (ALA) relies on the delta-6 desaturase (D6D) enzyme encoded by the Fads2 gene. While EPA and DHA reduce hepatic triacylglycerol (TAG) storage and regulate lipogenesis, the independent impact of ALA is less understood. To address this gap in knowledge, hepatic fatty acid metabolism was investigated in male wild-type (WT) and Fads2 knockout (KO) mice fed diets (16% kcal from fat) containing either lard (no n-3 LCPUFA), flaxseed oil (ALA-rich), or menhaden oil (EPA/DHA rich) for 21 weeks. Fat content and composition, as well as markers of lipogenesis, glyceroneogenesis, and TAG synthesis, were analyzed using histology, gas chromatography, and reverse transcription quantitative PCR (RT-qPCR). Mice fed the menhaden diet had significantly lower hepatic TAG compared to both lard- and flax-fed mice, concomitant with changes in n-3 and n-6 LCPUFA in both TAG and phospholipid (PL) fractions (all P < 0.05). Flax-fed WT mice had lower liver TAG content compared to their KO counterparts. Menhaden-fed mice had significantly lower expression of key lipogenic (Scd1, Srebp-1c, Fasn, Fads1, and Fads2), glyceroneogenic (Pck1), and TAG synthesis (Agpat3) genes compared to lard, with flax-fed mice showing some intermediate effects. Gene expression effects were independent of D6D activity, since no differences were detected between WT and KO mice fed the same diet. This study demonstrates that EPA/DHA and not ALA itself is critical for the prevention of hepatic steatosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100642"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gly-β-MCA is a potent anti-cholestasis agent against "human-like" hydrophobic bile acid-induced biliary injury in mice. Gly-β-MCA 是一种有效的抗胆汁淤积剂，可防止 "类人 "疏水胆汁酸引起的小鼠胆道损伤。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-09-19 DOI: 10.1016/j.jlr.2024.100649

Mohammad Nazmul Hasan, Huaiwen Wang, Wenyi Luo, Yung Dai Clayton, Lijie Gu, Yanhong Du, Sirish K Palle, Jianglei Chen, Tiangang Li

{"title":"Gly-β-MCA is a potent anti-cholestasis agent against \"human-like\" hydrophobic bile acid-induced biliary injury in mice.","authors":"Mohammad Nazmul Hasan, Huaiwen Wang, Wenyi Luo, Yung Dai Clayton, Lijie Gu, Yanhong Du, Sirish K Palle, Jianglei Chen, Tiangang Li","doi":"10.1016/j.jlr.2024.100649","DOIUrl":"10.1016/j.jlr.2024.100649","url":null,"abstract":"Cholestasis is a chronic liver disease with limited therapeutic options. Hydrophobic bile acid-induced hepatobiliary injury is a major pathological driver of cholestasis progression. This study investigates the anti-cholestasis efficacy and mechanisms of action of glycine-conjugated β-muricholic acid (Gly-β-MCA). We use female Cyp2c70 KO mice, a rodent cholestasis model that does not produce endogenous muricholic acid (MCA) and exhibits a \"human-like\" hydrophobic bile acid pool and female-dominant progressive hepatobiliary injury and portal fibrosis. The efficacy of Gly-β-MCA and ursodeoxycholic acid (UDCA), the first line drug for cholestasis, on cholangiopathy and portal fibrosis are compared. At a clinically relevant dose, Gly-β-MCA shows comparable efficacy as UDCA in reducing serum transaminase, portal inflammation and ductular reaction, and better efficacy than UDCA against portal fibrosis. Unlike endogenous bile acids, orally administered Gly-β-MCA is absorbed at low efficiency in the gut and enters the enterohepatic circulation mainly after microbiome-mediated deconjugation, which leads to taurine-conjugated MCA enrichment in bile that alters enterohepatic bile acid pool composition and reduces bile acid pool hydrophobicity. Gly-β-MCA also promotes fecal excretion of endogenous hydrophobic bile acids and decreases total bile acid pool size, while UDCA treatment does not alter total bile acid pool. Furthermore, Gly-β-MCA treatment leads to gut unconjugated MCA enrichment and reduces gut hydrophobic lithocholic acid (LCA) exposure. In contrast, UDCA treatment drives a marked increase of LCA flux through the large intestine. In conclusion, Gly-β-MCA is a potent anti-cholestasis agent with potential clinical application in treating human cholestasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100649"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Uterine prostaglandin DP receptor-induced upon implantation contributes to decidualization together with EP4 receptor. 植入后诱导的子宫前列腺素 DP 受体与 EP4 受体共同促进蜕膜化。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-01 Epub Date: 2024-08-31 DOI: 10.1016/j.jlr.2024.100636

Risa Sakamoto, Takuji Fujiwara, Yuko Kawano, Shizu Aikawa, Tomoaki Inazumi, On Nakayama, Yukiko Kawasaki-Shirata, Miho Hashimoto-Iwasaki, Toshiko Sugimoto, Soken Tsuchiya, Satohiro Nakao, Toru Takeo, Yasushi Hirota, Yukihiko Sugimoto

{"title":"Uterine prostaglandin DP receptor-induced upon implantation contributes to decidualization together with EP4 receptor.","authors":"Risa Sakamoto, Takuji Fujiwara, Yuko Kawano, Shizu Aikawa, Tomoaki Inazumi, On Nakayama, Yukiko Kawasaki-Shirata, Miho Hashimoto-Iwasaki, Toshiko Sugimoto, Soken Tsuchiya, Satohiro Nakao, Toru Takeo, Yasushi Hirota, Yukihiko Sugimoto","doi":"10.1016/j.jlr.2024.100636","DOIUrl":"10.1016/j.jlr.2024.100636","url":null,"abstract":"To investigate the yet-unknown roles of prostaglandins (PGs) in the uterus, we analyzed the expression of various PG receptors in the uterus. We found that three types of Gs-coupled PG receptors, DP, EP2, and EP4, were expressed in luminal epithelial cells from the peri-implantation period to late pregnancy. DP expression was also induced in stromal cells within the mesometrial region, whereas EP4 was expressed in stromal cells within the anti-mesometrial region during the peri-implantation period. The timing of DP induction after embryo attachment correlated well with that of cyclooxygenase-2 (COX-2); however, COX-2-expressing stromal cells were located in the vicinity of the embryo, whereas DP-expressing stromal cells surrounded these cells on the mesometrial side. Specific [3H]PGD2-binding activity was detected in the decidua of uteri, with PGD2 synthesis comparable to that of PGE2 detected in the uteri during the peri-implantation period. Administration of the COX-2-specific inhibitor celecoxib caused adverse effects on decidualization, as demonstrated by the attenuated weight of the implantation sites, which was recovered by the simultaneous administration of a DP agonist. Such a rescuing effect of the DP agonist was mimicked by an EP4 agonist, but not an EP2 agonist. While the importance of DP signaling was shown pharmacologically, DP/EP2 double deficiency did not affect implantation and decidualization, suggesting the contribution of EP4 to these processes. Indeed, administration of an EP4 antagonist substantially affected decidualization in DP/EP2-deficient mice. These results suggest that COX-2-derived PGD2 and PGE2 contribute to decidualization via a coordinated pathway of DP and EP4 receptors.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100636"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0