Journal of Lipid Research最新文献_第3页

Humanized Monoacylglycerol Acyltransferase 2 Mice Develop Metabolic Dysfunction-Associated Steatohepatitis. 人源化单酰甘油酰基转移酶 2 小鼠患上代谢功能障碍相关性脂肪性肝炎

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-11-04 DOI: 10.1016/j.jlr.2024.100695

Jose Corbalan, Pranavi Jagadeesan, Karla K Frietze, Rulaiha Taylor, Grace L Gao, Grant Gallagher, Joseph T Nickels

{"title":"Humanized Monoacylglycerol Acyltransferase 2 Mice Develop Metabolic Dysfunction-Associated Steatohepatitis.","authors":"Jose Corbalan, Pranavi Jagadeesan, Karla K Frietze, Rulaiha Taylor, Grace L Gao, Grant Gallagher, Joseph T Nickels","doi":"10.1016/j.jlr.2024.100695","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100695","url":null,"abstract":"Mice lacking monoacylglycerol acyltransferase 2 (mMGAT21) are resistant to diet-induced fatty liver, suggesting hMOGAT2 inhibition is a viable option for treating metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). We generated humanized hMOGAT2 mice (HuMgat2) for use in pre-clinical studies testing the efficacy of hMOGAT2 inhibitors for treating MASLD/MASH. HuMgat2 mice developed MASH when fed a steatotic diet. Computer-aided histology revealed the presence of hepatocyte cell ballooning, immune cell infiltration, and fibrosis. Hepatocytes accumulated Mallory-Denk bodies containing phosphorylated p62/sequestosome-1-ubiquintinated protein aggregates likely caused by defects in autophagy. Metainflammation and apoptotic cell death were seen in the livers of HuMgat2 mice. Treating HuMgat2 mice with elafibranor reduced several MASH phenotypes. RNASeq analysis predicted changes in bile acid transporter expression that correlated with altered bile acid metabolism indicative of cholestasis. Our results suggest that HuMgat2 mice will serve as a pre-clinical model for testing hMOGAT2 inhibitor efficacy and toxicity and allow for the study of hMOGAT2 in the context of MASH.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100695"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590909","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

Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells. 棕榈酸的脂肪毒性与肝细胞中 DGAT1 的下调有关，并因 PPARα 的激活而消失。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-11-04 DOI: 10.1016/j.jlr.2024.100692

Camilla Moliterni, Francesco Vari, Emily Schifano, Stefano Tacconi, Eleonora Stanca, Marzia Friuli, Serena Longo, Maria Conte, Stefano Salvioli, Davide Gnocchi, Antonio Mazzocca, Daniela Uccelletti, Daniele Vergara, Luciana Dini, Anna Maria Giudetti

{"title":"Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells.","authors":"Camilla Moliterni, Francesco Vari, Emily Schifano, Stefano Tacconi, Eleonora Stanca, Marzia Friuli, Serena Longo, Maria Conte, Stefano Salvioli, Davide Gnocchi, Antonio Mazzocca, Daniela Uccelletti, Daniele Vergara, Luciana Dini, Anna Maria Giudetti","doi":"10.1016/j.jlr.2024.100692","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100692","url":null,"abstract":"Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investigated the lipotoxicity of palmitic acid (PA), a saturated fatty acid, compared with oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and autophagy inhibition. Compared with OA, PA treatment leads to less lipid droplet (LD) accumulation and a significant reduction in the mRNA and protein level of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of triacylglycerol synthesis. Using modulators of ER stress and autophagy, we established that DGAT1 downregulation by PA is closely linked to these cellular pathways. Notably, the ER stress inhibitor 4-phenylbutyrate can suppress PA-induced DGAT1 downregulation. Furthermore, knockdown of DGAT1 by siRNA or with A922500, a specific DGAT1 inhibitor, resulted in cell death, even with OA. Both PA and OA increased the oxygen consumption rate; however, the increase associated with PA was only partially coupled to ATP synthesis. Importantly, treatment with GW7647 a specific PPARα agonist mitigated the lipotoxic effects of PA, restoring PA-induced ER stress, autophagy block, and DGAT1 suppression. In conclusion, our study highlights the crucial role of DGAT1 in PA-induced lipotoxicity, broadening the knowledge of the mechanisms underlying hepatic lipotoxicity and providing the basis for potential therapeutic interventions.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100692"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590911","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

ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis. ACAT1/SOAT1 通过调节胆固醇平衡维持前脂肪细胞的成脂能力。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-29 DOI: 10.1016/j.jlr.2024.100680

Qing Liu, Xiaolin Wu, Wei Duan, Xiaohan Pan, Martin Wabitsch, Ming Lu, Jing Li, Li-Hao Huang, Zhangsen Zhou, Yuyan Zhu

{"title":"ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis.","authors":"Qing Liu, Xiaolin Wu, Wei Duan, Xiaohan Pan, Martin Wabitsch, Ming Lu, Jing Li, Li-Hao Huang, Zhangsen Zhou, Yuyan Zhu","doi":"10.1016/j.jlr.2024.100680","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100680","url":null,"abstract":"Maintaining cholesterol homeostasis is critical for preserving adipocyte function during the progression of obesity. Despite this, the regulatory role of cholesterol esterification in governing adipocyte expandability has been understudied. Acyl-coenzyme A (CoA):cholesterol acyltransferase / Sterol O-acyltransferase 1 (ACAT1/SOAT1) is the dominant enzyme to synthesize cholesteryl ester in most tissues. Our previous study demonstrated that knockdown of either ACAT1 or ACAT2 impaired adipogenesis. However, the underlying mechanism of how ACAT1 mediates adipogenesis remains unclear. Here, we reported that ACAT1 is the dominant isoform in white adipose tissue of both humans and mice and knocking out ACAT1 reduced fat mass in mice. Furthermore, ACAT1-deficiency inhibited the early stage of adipogenesis via attenuating PPARγ pathway. Mechanistically, ACAT1 deficiency inhibited SREBP2-mediated cholesterol uptake and thus reduced intracellular and plasma membrane cholesterol level during adipogenesis. While replenishing cholesterol could rescue adipogenic master gene - Pparγ's transcription in ACAT1 deficient cells during adipogenesis. Finally, overexpression of catalytically functional ACAT1, not the catalytic-dead ACAT1, rescued cholesterol level and efficiently rescued the transcription of PPARγ, as well as the adipogenesis in ACAT1-deficient preadipocytes. In summary, our study revealed the indispensable role of ACAT1 in adipogenesis via regulating intracellular cholesterol homeostasis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100680"},"PeriodicalIF":5.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558068","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

Effects of coconut oil, olive oil, and butter on plasma fatty acids and metabolic risk factors: a randomized trial. 椰子油、橄榄油和黄油对血浆脂肪酸和代谢风险因素的影响：随机试验。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-28 DOI: 10.1016/j.jlr.2024.100681

Solomon A Sowah, Albert Koulman, Stephen J Sharp, Fumiaki Imamura, Kay-Tee Khaw, Nita G Forouhi

{"title":"Effects of coconut oil, olive oil, and butter on plasma fatty acids and metabolic risk factors: a randomized trial.","authors":"Solomon A Sowah, Albert Koulman, Stephen J Sharp, Fumiaki Imamura, Kay-Tee Khaw, Nita G Forouhi","doi":"10.1016/j.jlr.2024.100681","DOIUrl":"10.1016/j.jlr.2024.100681","url":null,"abstract":"There is limited evidence on the effects of different dietary sources of fats on detailed blood fatty acids (FAs). We aimed to evaluate the effects of coconut oil, olive oil and butter on circulating FA concentrations, and examine the associations between changes in plasma FAs and changes in metabolic markers. We conducted secondary analyses in the COB (coconut oil, olive oil and butter) Trial that evaluated 96 healthy adults in a 4-week parallel randomized clinical trial of three dietary interventions: 50 g/d of extra-virgin coconut oil (n = 30), extra-virgin olive oil (n = 33), or unsalted butter (n = 33). We measured plasma phospholipid FA concentrations (mol% of total) using gas chromatography. Using linear regression, we estimated the effects of the interventions on changes in FAs and the associations of changes in selected FAs with changes in metabolic markers. Coconut oil doubled lauric acid (C12:0) and myristic acid (C14:0), butter increased those to a lesser extent, and olive oil reduced those. β (95% confidence interval) for changes in C12:0 comparing coconut oil to butter and olive oil were +0.04 (0.03-0.05) and +0.05 (0.04-0.06) mol%, respectively; for C14:0, +0.24 (0.17-0.32) and +0.37 (0.29-0.45), respectively. Olive oil increased oleic acid (OA) approximately by 1 mol%, while coconut oil and butter had little effect on OA. Butter increased odd-chain SFAs and trans-FAs while olive oil and coconut oil decreased them. Changes in FAs mostly showed no significant associations with changes in metabolic markers. The interventions of equal amounts of different food FA sources altered circulating FA concentrations differently.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100681"},"PeriodicalIF":5.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568849","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

Diet, β-glucocerebrosidase deficiency, and Parkinson's disease. 饮食、β-葡糖脑苷脂缺乏症和帕金森病。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-28 DOI: 10.1016/j.jlr.2024.100689

James A Shayman

引用次数: 0

APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1. APOA2 通过置换驻留 APOA1 的 C-末端来增加血浆高密度脂蛋白的胆固醇外排能力。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-28 DOI: 10.1016/j.jlr.2024.100686

Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E Street, Stephanie M Thibert, Isaac K Attah, Chelsea M Hutchinson Bunch, Irina V Novikova, James E Evans, Amy S Shah, Scott M Gordon, Jere P Segrest, Karin E Bornfeldt, Tomas Vaisar, Jay W Heinecke, W Sean Davidson, John T Melchior

{"title":"APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1.","authors":"Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E Street, Stephanie M Thibert, Isaac K Attah, Chelsea M Hutchinson Bunch, Irina V Novikova, James E Evans, Amy S Shah, Scott M Gordon, Jere P Segrest, Karin E Bornfeldt, Tomas Vaisar, Jay W Heinecke, W Sean Davidson, John T Melchior","doi":"10.1016/j.jlr.2024.100686","DOIUrl":"10.1016/j.jlr.2024.100686","url":null,"abstract":"The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up experiments with reconstituted HDL corroborated that the presence of both APOA1 and APOA2 were necessary for the increased efflux. Using limited proteolysis and chemical cross-linking mass spectrometry, we found that APOA2 induced a conformational change in the N- and C-terminal helices of APOA1. Using reconstituted HDL with APOA1 deletion mutants, we further showed that APOA2 lost its ability to stimulate ABCA1 efflux to HDL if the C-terminal domain of APOA1 was absent, but retained this ability when the N-terminal domain was absent. Based on these findings, we propose a model in which APOA2 displaces the C-terminal helix of APOA1 from the HDL surface which can then interact with ABCA1-much like it does in lipid-poor APOA1. These findings suggest APOA2 may be a novel therapeutic target given this ability to open a large, high-capacity pool of HDL particles to enhance ABCA1-mediated cholesterol efflux.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100686"},"PeriodicalIF":5.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568843","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

Impact of maternal health and stress on steroid hormone profiles in human milk: Implications for infant development. 产妇健康和压力对母乳中类固醇激素谱的影响：对婴儿发育的影响。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-26 DOI: 10.1016/j.jlr.2024.100688

Isabel Ten-Doménech, Alba Moreno-Giménez, Laura Campos-Berga, Cristina Zapata de Miguel, Marina López-Nogueroles, Anna Parra-Llorca, Guillermo Quintás, Ana García-Blanco, María Gormaz, Julia Kuligowski

{"title":"Impact of maternal health and stress on steroid hormone profiles in human milk: Implications for infant development.","authors":"Isabel Ten-Doménech, Alba Moreno-Giménez, Laura Campos-Berga, Cristina Zapata de Miguel, Marina López-Nogueroles, Anna Parra-Llorca, Guillermo Quintás, Ana García-Blanco, María Gormaz, Julia Kuligowski","doi":"10.1016/j.jlr.2024.100688","DOIUrl":"10.1016/j.jlr.2024.100688","url":null,"abstract":"Steroid hormones are biologically active factors in human milk (HM) that influence the physical and mental development of infants. Critically, maternal psychosocial stress has been associated with changes in HM steroid composition. This work aimed to characterize the steroid hormone profile of HM and pasteurized donor human milk (DHM) and assess the interplay between maternal physical and psychosocial status, the HM steroid profile, and infant outcomes. A targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to quantify sixteen steroid hormones in HM samples. HM samples from mothers of term infants (N = 42) and preterm infants (N = 35) were collected at (i) recovery of birth weight or achievement of complete enteral nutrition, respectively, and (ii) 6 months later as well as DHM samples (N = 19) from 11 donors. The physical and psychosocial status of mothers and infant neurodevelopment and temperament were assessed through structured interviews and validated questionnaires. Fourteen steroids were detected in HM/DHM samples, with cortisol, 20β-dihydrocortisol, dehydroepiandrosterone, pregnenolone, and cortisone being present in > 48% of samples. Pregnenolone, 17α-OH-progesterone, and dehydroepiandrosterone are reported for the first time in HM. Whereas milk cortisol levels were not directly related to maternal physical and psychosocial status nor with infant development, cortisone, and pregnenolone correlated positively with maternal weight gain during pregnancy and were associated with maternal well-being and infant growth. The pasteurization process may have a detrimental effect on the steroid hormone levels in HM, which might influence the development of receptors.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100688"},"PeriodicalIF":5.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568851","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

Toxoplasma gondii Sustains Survival by Regulating Cholesterol Biosynthesis and Uptake via SREBP2 Activation. 弓形虫通过 SREBP2 激活调节胆固醇的合成和吸收维持生存

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100684

Yi-Min Fan, Qing-Qi Zhang, Ming Pan, Zhao-Feng Hou, Lizhi Fu, Xiulong Xu, Si-Yang Huang

{"title":"Toxoplasma gondii Sustains Survival by Regulating Cholesterol Biosynthesis and Uptake via SREBP2 Activation.","authors":"Yi-Min Fan, Qing-Qi Zhang, Ming Pan, Zhao-Feng Hou, Lizhi Fu, Xiulong Xu, Si-Yang Huang","doi":"10.1016/j.jlr.2024.100684","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100684","url":null,"abstract":"Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that cannot biosynthesize cholesterol via the mevalonate pathway, it sources this lipid from its host. We discovered that T. gondii infection upregulated the expression of host cholesterol synthesis related genes HMG-CoA reductase(HMGCR), squalene epoxidase (SQLE) and dehydrocholesterol reductase-7 (DHCR7), and increased the uptake pathway gene low-density lipoprotein receptor (LDLR). We found a protein, sterol regulatory element binding protein 2 (SREBP2), which is the key protein regulating the host cholesterol synthesis and uptake during T. gondii infection. T. gondii induced a dose-dependent nuclear translocation of SREBP2. Knockdown SREBP2 reduced T. gondii-induced cholesterol biosynthesis and uptake. Consequently, the parasite's ability to acquire cholesterol was significantly diminished, impairing its invasion, replication, and bradyzoites development. Interfering cholesterol metabolism using AY9944 effectively inhibited T. gondii replication. In summary, SREBP2 played an important role in T. gondii infection in vitro, serving as a potential target for regulating T. gondii-induced cholesterol metabolism, offering insights into the prevention and treatment of toxoplasmosis.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100684"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568869","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

Differential impact of eicosapentaenoic acid and docosahexaenoic acid in an animal model of Alzheimer's disease. 二十碳五烯酸和二十二碳六烯酸对阿尔茨海默病动物模型的不同影响

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100682

Méryl-Farelle Oye Mintsa Mi-Mba, Meryem Lebbadi, Waël Alata, Carl Julien, Vincent Emond, Cyntia Tremblay, Samuel Fortin, Colin J Barrow, Jean-François Bilodeau, Frédéric Calon

{"title":"Differential impact of eicosapentaenoic acid and docosahexaenoic acid in an animal model of Alzheimer's disease.","authors":"Méryl-Farelle Oye Mintsa Mi-Mba, Meryem Lebbadi, Waël Alata, Carl Julien, Vincent Emond, Cyntia Tremblay, Samuel Fortin, Colin J Barrow, Jean-François Bilodeau, Frédéric Calon","doi":"10.1016/j.jlr.2024.100682","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100682","url":null,"abstract":"Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) improves cognitive performance in several animal models of Alzheimer's disease (AD), an effect often associated with reduced amyloid-beta (Aβ) and/or tau pathologies. However, it remains unclear to what extent eicosapentaenoic (EPA) provides additional benefits compared to docosahexaenoic acid (DHA). Here, male and female 3xTg-AD mice were fed for 3 months (13 to 16 months of age) the following diets: (1) control (no DHA/EPA), (2) DHA (1.1g/kg) and low EPA (0.4g/kg), or (3) DHA (0.9g/kg) with high EPA (9.2g/kg). The DHA and DHA+EPA diets respectively increased DHA by 19% and 8% in the frontal cortex of 3xTg-AD mice, compared to controls. Levels of EPA, which were below the detection limit after the control diet, reached 0.14% and 0.29% of total brain fatty acids after the DHA and DHA+EPA diet, respectively. DHA and DHA+EPA diets lowered brain arachidonic acid (ARA) levels and the n-6:n-3 docosapentaenoic acid (DPA) ratio. Brain uptake of free 14C-DHA measured through intracarotid brain perfusion, but not of 14C-EPA, was lower in 3xTg-AD compared to NonTg mice. DHA and DHA+EPA diets in 3xTg-AD mice reduced cortical soluble phosphorylated tau (pS202) (-34% high-DHA, -34% DHA+EPA, p<0.05) while increasing p21 activated kinase (+58% and +83%, p<0.001; respectively). High EPA intake lowered insoluble phosphorylated tau (-31% versus DHA, p<0.05). No diet effect on Aβ levels was observed. In conclusion, dietary intake of DHA and EPA leads to differential changes in brain PUFA while altering cerebral biomarkers consistent with beneficial effects against AD-like neuropathology.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100682"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568848","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

Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation. Orm 蛋白通过 LCB 介导的 Ypk1 调节来控制神经酰胺的合成和内吞。

IF 5 2区医学

Journal of Lipid Research Pub Date : 2024-10-25 DOI: 10.1016/j.jlr.2024.100683

Jihui Ren, Robert Rieger, Nivea Pereira de Sa, Douglas Kelapire, Maurizio Del Poeta, Yusuf A Hannun

{"title":"Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation.","authors":"Jihui Ren, Robert Rieger, Nivea Pereira de Sa, Douglas Kelapire, Maurizio Del Poeta, Yusuf A Hannun","doi":"10.1016/j.jlr.2024.100683","DOIUrl":"https://doi.org/10.1016/j.jlr.2024.100683","url":null,"abstract":"Sphingolipids (SPLs) are major components of cell membranes with significant functions. Their production is a highly-regulated multi-step process with the formation of two major intermediates, long chain bases (LCBs) and ceramides. Homologous Orm proteins in both yeast and mammals negatively regulate LCB production by inhibiting serine palmitoyltransferase (SPT), the first enzyme in SPL de novo synthesis. Orm proteins are therefore regarded as major regulator of SPL production. Combining targeted lipidomic profiling with phenotypic analysis of yeast mutants with both ORM1 and ORM2 deleted (orm1/2Δ), we report here that Ypk1, an AGC family protein kinase, signaling is compromised in an LCB-dependent manner. In orm1/2Δ, phosphorylation of Ypk1 at its activation sites is reduced, so does its in vivo activity shown by reduced phosphorylation of Ypk1 substrate, Lac1, the catalytic component of ceramide synthase (CerS). A corresponding defect in ceramide synthesis was detected, preventing the extra LCBs generated in orm1/2Δ from fully converting into downstream SPL products. The results suggest that Orm proteins play a complex role in regulating SPL production in yeast S. cerevisiae by exerting an extra and opposite effect on CerS. Functionally, we define an endocytosis and an actin polarization defect of orm1/2Δ and demonstrate the roles of Ypk1 in mediating the effects of Orm proteins on endocytosis. Collectively, the results reveal a previously unrecognized complexity of SPL de novo synthesis pathway and point to a potential role of Orm proteins as upstream regulators to control Ypk1-mediated biological functions via regulating LCB production.","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100683"},"PeriodicalIF":5.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568860","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