Journal of Lipid Research最新文献

{"title":"Lipidomic and metabolomic changes in community-acquired and COVID-19 pneumonia.","authors":"Mireia Saballs, Sandra Parra, Neus Martínez, Nuria Amigo, Lydia Cabau, Simona Iftimie, Raul Pavon, Xavi Gabaldó, Xavier Correig, Silvia Paredes, Josep Maria Vallvé, Antoni Castro","doi":"10.1016/j.jlr.2024.100622","DOIUrl":"10.1016/j.jlr.2024.100622","url":null,"abstract":"<p><p>This prospective observational study compared the 1H NMR blood lipidomes and metabolomes of 71 patients with community-acquired pneumonia (CAP), 75 patients with COVID-19 pneumonia, and 75 healthy controls (matched by age and sex) to identify potential biomarkers and pathways associated with respiratory infections. Both pneumonia groups had comparable severity indices, including mortality, invasive mechanical ventilation, and intensive care unit admission rates. Patients with COVID-19 pneumonia exhibited more pronounced hypolipidemia, with significantly lower levels of total cholesterol and LDL-c compared to patients with CAP. Atherogenic lipoprotein subclasses (VLDL-cholesterol, IDL-cholesterol, IDL-triglyceride, and LDL-triglyceride/LDL-cholesterol) were significantly increased in severe cases of both pneumonia types, while lower HDL-c and small, dense HDL particles were associated with more severe illness. Both infected groups showed decreased esterified cholesterol and increased triglycerides, along with reduced phosphatidylcholine, lysophosphatidylcholine, PUFA, omega-3 fatty acids, and DHA. Additionally, infected patients had elevated levels of glucose, lactate, 3-hydroxybutyrate, and acetone, which are linked to inflammation, hypoxemia, and sepsis. Increased levels of branched-chain amino acids, alanine, glycine, and creatine, which are involved in energy metabolism and protein catabolism, were also observed. Neurotransmitter synthesis metabolites like histidine and glutamate were higher in infected patients, especially those with COVID-19. Notably, severe infections showed a significant decrease in glutamine, essential for lymphocyte and macrophage energy. The severity of COVID-19 pneumonia was also associated with elevated glycoprotein levels (glycoprotein A, glycoprotein B, and glycoprotein F), indicating an inflammatory state. These findings suggest that metabolomic and lipidomic changes in pneumonia are connected to bioenergetic pathways regulating the immune response.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100622"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11422144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000045","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}

{"title":"Polyunsaturated fatty acids stimulate immunity and eicosanoid production in Drosophila melanogaster.","authors":"Pakeeza Azizpor, Ogadinma K Okakpu, Sophia C Parks, Diego Chavez, Fayez Eyabi, Stephanie Martinez-Beltran, Susan Nguyen, Adler R Dillman","doi":"10.1016/j.jlr.2024.100608","DOIUrl":"10.1016/j.jlr.2024.100608","url":null,"abstract":"<p><p>Eicosanoids are a class of molecules derived from C20 polyunsaturated fatty acids (PUFAs) that play a vital role in mammalian and insect biological systems, including development, reproduction, and immunity. Recent research has shown that insects have significant but lower levels of C20 PUFAs in circulation in comparison to C18 PUFAs. It has been previously hypothesized in insects that eicosanoids are synthesized from C18 precursors, such as linoleic acid (LA), to produce downstream eicosanoids. In this study, we show that introduction of arachidonic acid (AA) stimulates production of cyclooxygenase, lipoxygenase, and cytochrome P450-derived eicosanoids. Downstream immune readouts showed that LA stimulates phagocytosis by hemocytes, while both LA and AA stimulate increased antimicrobial peptide production when D. melanogaster is exposed to a heat-killed bacterial pathogen. In totality, this work identifies PUFAs that are involved in insect immunity and adds evidence to the notion that Drosophila utilizes immunostimulatory lipid signaling to mitigate bacterial infections. Our understanding of immune signaling in the fly and its analogies to mammalian systems will increase the power and value of Drosophila as a model organism in immune studies.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100608"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11386307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788315","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}

{"title":"Pioglitazone alleviates lacrimal gland impairments induced by high-fat diet by suppressing M1 polarization.","authors":"Yu-Qing Chen, Yu-Chao Shao, Rui-Li Wei","doi":"10.1016/j.jlr.2024.100606","DOIUrl":"10.1016/j.jlr.2024.100606","url":null,"abstract":"<p><p>A high-fat diet (HFD) contributes to the pathogenesis of various inflammatory and metabolic diseases. Previous research confirms that under HFD conditions, the extraorbital lacrimal glands (ELGs) can be impaired, with significant infiltration of pro-inflammatory macrophages (Mps). However, the relationship between HFD and Mps polarization in the ELGs remains unexplored. We first identified and validated the differential expression of PPAR-γ in murine ELGs fed ND and HFD through RNA sequencing. Tear secretion was measured using the Schirmer test. Lipid droplet deposition within the ELGs was observed through Oil Red O staining and transmission electron microscopy. Mps phenotypes were determined through quantitative RT-PCR, immunofluorescence, and flow cytometric analysis. An in vitro high-fat culture system for Mps was established using palmitic acid (PA), with supernatants collected for co-culture with lacrimal gland acinar cells. Gene expression was determined through ELISA, immunofluorescence, immunohistochemistry, quantitative RT-PCR, and Western blot analysis. Pioglitazone reduced M1-predominant infiltration induced by HFD by increasing PPAR-γ levels in ELGs, thereby alleviating lipid deposition and enhancing tear secretion. In vitro tests indicated that PPAR-γ agonist shifted Mps from M1-predominant to M2-predominant phenotype in PA-induced Mps, reducing lipid synthesis in LGACs and promoting lipid catabolism, thus alleviating lipid metabolic disorders within ELGs. Conversely, the PPAR-γ antagonist induced opposite effects. In summary, the lacrimal gland is highly sensitive to high-fat and lipid metabolic disorders. Downregulation of PPAR-γ expression in ELGs induces Mps polarization toward predominantly M1 phenotype, leading to lipid metabolic disorder and inflammatory responses via the NF-κb/ERK/JNK/P38 pathway.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100606"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11386124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788314","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}

{"title":"SCD4 deficiency decreases cardiac steatosis and prevents cardiac remodeling in mice fed a high-fat diet.","authors":"Marcin Wolosiewicz, Volodymyr V Balatskyi, Monika K Duda, Anna Filip, James M Ntambi, Viktor O Navrulin, Pawel Dobrzyn","doi":"10.1016/j.jlr.2024.100612","DOIUrl":"10.1016/j.jlr.2024.100612","url":null,"abstract":"<p><p>Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that catalyzes formation of the first double bond in the carbon chain of saturated fatty acids. Four isoforms of SCD have been identified in mice, the most poorly characterized of which is SCD4, which is cardiac-specific. In the present study, we investigated the role of SCD4 in systemic and cardiac metabolism. We used WT and global SCD4 KO mice that were fed standard laboratory chow or a high-fat diet (HFD). SCD4 deficiency reduced body adiposity and decreased hyperinsulinemia and hypercholesterolemia in HFD-fed mice. The loss of SCD4 preserved heart morphology in the HFD condition. Lipid accumulation decreased in the myocardium in SCD4-deficient mice and in HL-1 cardiomyocytes with knocked out Scd4 expression. This was associated with an increase in the rate of lipolysis and, more specifically, adipose triglyceride lipase (ATGL) activity. Possible mechanisms of ATGL activation by SCD4 deficiency include lower protein levels of the ATGL inhibitor G0/G1 switch protein 2 and greater activation by protein kinase A under lipid overload conditions. Moreover, we observed higher intracellular Ca²⁺ levels in HL-1 cells with silenced Scd4 expression. This may explain the activation of protein kinase A in response to higher Ca²⁺ levels. Additionally, the loss of SCD4 inhibited mitochondrial enlargement, NADH overactivation, and reactive oxygen species overproduction in the heart in HFD-fed mice. In conclusion, SCD4 deficiency activated lipolysis, resulting in a reduction of cardiac steatosis, prevented the induction of left ventricular hypertrophy, and reduced reactive oxygen species levels in the heart in HFD-fed mice.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100612"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878861","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}

{"title":"The lipidomics reporting checklist a framework for transparency of lipidomic experiments and repurposing resource data.","authors":"Dominik Kopczynski, Christer S Ejsing, Jeffrey G McDonald, Takeshi Bamba, Erin S Baker, Justine Bertrand-Michel, Britta Brügger, Cristina Coman, Shane R Ellis, Timothy J Garrett, William J Griffiths, Xue Li Guan, Xianlin Han, Marcus Höring, Michal Holčapek, Nils Hoffmann, Kevin Huynh, Rainer Lehmann, Jace W Jones, Rima Kaddurah-Daouk, Harald C Köfeler, Peter J Meikle, Thomas O Metz, Valerie B O'Donnell, Daisuke Saigusa, Dominik Schwudke, Andrej Shevchenko, Federico Torta, Juan Antonio Vizcaíno, Ruth Welti, Markus R Wenk, Denise Wolrab, Yu Xia, Kim Ekroos, Robert Ahrends, Gerhard Liebisch","doi":"10.1016/j.jlr.2024.100621","DOIUrl":"10.1016/j.jlr.2024.100621","url":null,"abstract":"<p><p>The rapid increase in lipidomic studies has led to a collaborative effort within the community to establish standards and criteria for producing, documenting, and disseminating data. Creating a dynamic easy-to-use checklist that condenses key information about lipidomic experiments into common terminology will enhance the field's consistency, comparability, and repeatability. Here, we describe the structure and rationale of the established Lipidomics Minimal Reporting Checklist to increase transparency in lipidomics research.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100621"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995865","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}

{"title":"Mechanistic insights into metabolic function of dynamin-related protein 1.","authors":"Xin Li, Katherine Pham, Jazmin Ysaguirre, Iqbal Mahmud, Lin Tan, Bo Wei, Long J Shao, Maryam Elizondo, Rabie Habib, Fathima Elizondo, Hiromi Sesaki, Philip L Lorenzi, Kai Sun","doi":"10.1016/j.jlr.2024.100633","DOIUrl":"10.1016/j.jlr.2024.100633","url":null,"abstract":"<p><p>Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, DRP1 deficiency induced the retention of nascent lipid droplets in ER, leading to perturbed overall lipid dynamics in the KO mice. Collectively, dysregulation of the dynamics of mitochondria, ER, and lipid droplets contributes to whole-body metabolic disorders, as evidenced by perturbations in energy metabolites. Our findings demonstrate that DRP1 plays diverse and critical roles in regulating energy metabolism within adipose tissue during the progression of obesity.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100633"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055755","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}

{"title":"A high-resolution ¹³C NMR approach for profiling fatty acid unsaturation in lipid extracts and in live Caenorhabditiselegans.","authors":"Bruno Hernández Cravero, Gastón Prez, Verónica A Lombardo, Florencia V Guastaferri, Carla B Delprato, Silvia Altabe, Diego de Mendoza, Andres Binolfi","doi":"10.1016/j.jlr.2024.100618","DOIUrl":"10.1016/j.jlr.2024.100618","url":null,"abstract":"<p><p>Unsaturated fatty acids (UFA) play a crucial role in central cellular processes in animals, including membrane function, development, and disease. Disruptions in UFA homeostasis can contribute to the onset of metabolic, cardiovascular, and neurodegenerative disorders. Consequently, there is a high demand for analytical techniques to study lipid compositions in live cells and multicellular organisms. Conventional analysis of UFA compositions in cells, tissues, and organisms involves solvent extraction procedures coupled with analytical techniques such as gas chromatography, MS and/or NMR spectroscopy. As a nondestructive and nontargeted technique, NMR spectroscopy is uniquely capable of characterizing the chemical profiling of living cells and multicellular organisms. Here, we use NMR spectroscopy to analyze Caenorhabditis elegans, enabling the determination of their lipid compositions and fatty acid unsaturation levels both in cell-free lipid extracts and in vivo. The NMR spectra of lipid extracts from WT and fat-3 mutant C. elegans strains revealed notable differences due to the absence of Δ-6 fatty acid desaturase activity, including the lack of arachidonic and eicosapentaenoic acyl chains. Uniform ¹³C-isotope labeling and high-resolution 2D solution-state NMR of live worms confirmed these findings, indicating that the signals originated from fast-tumbling lipid molecules within lipid droplets. Overall, this strategy permits the analysis of lipid storage in intact worms and has enough resolution and sensitivity to identify differences between WT and mutant animals with impaired fatty acid desaturation. Our results establish methodological benchmarks for future investigations of fatty acid regulation in live C. elegans using NMR.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100618"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912974","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}

{"title":"The metabolic signature of blood lipids: a causal inference study using twins.","authors":"Yutong Wang, Shunkai Liu, Weihua Cao, Jun Lv, Canqing Yu, Tao Huang, Dianjianyi Sun, Chunxiao Liao, Yuanjie Pang, Zengchang Pang, Min Yu, Hua Wang, Xianping Wu, Yu Liu, Wenjing Gao, Liming Li","doi":"10.1016/j.jlr.2024.100625","DOIUrl":"10.1016/j.jlr.2024.100625","url":null,"abstract":"<p><p>Dyslipidemia is one of the cardiometabolic risk factors that influences mortality globally. Unraveling the causality between blood lipids and metabolites and the complex networks connecting lipids, metabolites, and other cardiometabolic traits can help to more accurately reflect the body's metabolic disorders and even cardiometabolic diseases. We conducted targeted metabolomics of 248 metabolites in 437 twins from the Chinese National Twin Registry. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) analysis was used for causal inference between metabolites and lipid parameters. Bidirectional mediation analysis was performed to explore the linkages between blood lipids, metabolites, and other seven cardiometabolic traits. We identified 44, 1, and 31 metabolites associated with triglyceride (TG), total cholesterol (TC), and high-density lipoprotein-cholesterol (HDL-C), most of which were gut microbiota-derived metabolites. There were 9, 1, and 14 metabolites that showed novel associations with TG, TC, and HDL-C, respectively. ICE FALCON analysis found that TG and HDL-C may have a predicted causal effect on 23 and six metabolites, respectively, and one metabolite may have a predicted causal effect on TG. Mediation analysis discovered 14 linkages connecting blood lipids, metabolites, and other cardiometabolic traits. Our study highlights the significance of gut microbiota-derived metabolites in lipid metabolism. Most of the identified cross-sectional associations may be due to the lipids having a predicted causal effect on metabolites, but not vice versa, nor are they due to family confounding. These findings shed new light on lipid metabolism and personalized management of cardiometabolic diseases.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":"65 9","pages":"100625"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289306","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}

{"title":"Temporal dissociation of COX-2-dependent arachidonic acid and 2-arachidonoylglycerol metabolism in RAW264.7 macrophages.","authors":"Ansari M Aleem, Michelle M Mitchener, Philip J Kingsley, Carol A Rouzer, Lawrence J Marnett","doi":"10.1016/j.jlr.2024.100615","DOIUrl":"10.1016/j.jlr.2024.100615","url":null,"abstract":"<p><p>Cyclooxygenase-2 converts arachidonic acid to prostaglandins (PGs) and the endocannabinoid, 2-arachidonoylglycerol (2-AG), to PG glyceryl esters (PG-Gs). The physiological function of PG biosynthesis has been extensively studied, but the importance of the more recently discovered PG-G synthetic pathway remains incompletely defined. This disparity is due in part to a lack of knowledge of the physiological conditions under which PG-G biosynthesis occurs. We have discovered that RAW264.7 macrophages stimulated with Kdo2-lipid A (KLA) produce primarily PGs within the first 12 h followed by robust PG-G synthesis between 12 h and 24 h. We suggest that the amount of PG-Gs quantified is less than actually synthesized, because PG-Gs are subject to a significant level of hydrolysis during the time course of synthesis. Inhibition of cytosolic phospholipase A2 by giripladib does not accelerate PG-G synthesis, suggesting the differential time course of PG and PG-G synthesis is not due to the competition between arachidonic acid and 2-AG. The late-phase PG-G formation is accompanied by an increase in the level of 2-AG and a concomitant decrease in 18:0-20:4 diacylglycerol (DAG). Inhibition of DAG lipases by KT-172 decreases the levels of 2-AG and PG-Gs, indicating that the DAG-lipase pathway is involved in delayed 2-AG metabolism/PG-G synthesis. These results demonstrate that physiologically significant levels of PG-Gs are produced by activated RAW264.7 macrophages well after the production of PGs plateaus.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100615"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11401187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889435","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}

{"title":"Abcb4-defect cholangitis mouse model with hydrophobic bile acid composition by in vivo liver-specific gene deletion.","authors":"Kota Tsuruya, Keiko Yokoyama, Yusuke Mishima, Kinuyo Ida, Takuma Araki, Satsuki Ieda, Masato Ohtsuka, Yutaka Inagaki, Akira Honda, Tatehiro Kagawa, Akihide Kamiya","doi":"10.1016/j.jlr.2024.100616","DOIUrl":"10.1016/j.jlr.2024.100616","url":null,"abstract":"<p><p>Progressive familial intrahepatic cholestasis (PFIC) is a liver disease that occurs during childhood and requires liver transplantation. ABCB4 is localized along the canalicular membranes of hepatocytes, transports phosphatidylcholine into bile, and its mutation causes PFIC3. Abcb4 gene-deficient mice established as animal models of PFIC3 exhibit cholestasis-induced liver injury. However, their phenotypes are often milder than those of human PFIC3, partly because of the existence of large amounts of less toxic hydrophilic bile acids synthesized by the rodent-specific enzymes Cyp2c70 and Cyp2a12. Mice with double deletions of Cyp2c70/Cyp2a12 (CYPDKO mice) have a human-like hydrophobic bile acid composition. PFIC-related gene mutations were induced in CYPDKO mice to determine whether these triple-gene-deficient mice are a better model for PFIC. To establish a PFIC3 mouse model using CYPDKO mice, we induced abcb4 gene deletion in vivo using adeno-associated viruses expressing SaCas9 under the control of a liver-specific promoter and abcb4-target gRNAs. Compared to Abcb4-deficient wild-type mice, Abcb4-deficient CYPDKO mice showed more pronounced liver injury along with an elevation of inflammatory and fibrotic markers. The proliferation of intrahepatic bile ductal cells and hematopoietic cell infiltration were also observed. CYPDKO/abcb4-deficient mice show a predominance of taurine-conjugated chenodeoxycholic acid and lithocholic acid in the liver. In addition, phospholipid levels in the gallbladder bile were barely detectable. Mice with both human-like bile acid composition and Abcb4-defect exhibit severe cholestatic liver injury and are useful for studying human cholestatic diseases and developing new treatments.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100616"},"PeriodicalIF":5.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901967","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}