Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献

{"title":"Differentiating human phospholipase A2's activity toward phosphatidylinositol, phosphatidylinositol phosphate and phosphatidylinositol bisphosphate","authors":"Daiki Hayashi ,&nbsp;Edward A. Dennis","doi":"10.1016/j.bbalip.2024.159527","DOIUrl":"10.1016/j.bbalip.2024.159527","url":null,"abstract":"<div><p>Phospholipase A₂'s (PLA₂'s) constitute a superfamily of enzymes that hydrolyze the <em>sn</em>-2 fatty acyl chain on glycerophospholipids. We have previously reported that each PLA₂ Type shows a unique substrate specificity for the molecular species it hydrolyzes, especially the acyl chain that is cleaved from the <em>sn</em>-2 position and to some extent the polar group. However, phosphatidylinositol (PI) and PI phosphates (PIPs) have not been as well studied as substrates as other phospholipids because the PIPs require adaptation of the standard analysis methods, but they are important <em>in vivo</em>. We determined the <em>in vitro</em> activity of the three major types of human PLA₂'s, namely the cytosolic (c), calcium-independent (i), and secreted (s) PLA₂^'s toward PI, PI-4-phosphate (PI(4)P), and PI-4,5-bisphosphate (PI(4,5)P₂). The <em>in vitro</em> assay revealed that Group IVA cPLA₂ (GIVA cPLA₂) showed relatively high activity toward PI and PI(4)P among the tested PLA₂'s; nevertheless, the highly hydrophilic headgroup disrupted the interaction between the lipid surface and the enzyme. GIVA cPLA₂ and GVIA iPLA₂ showed detectable activity toward PI(4,5)P₂, but it appeared to be a poorer substrate for all of the PLA₂'s tested. Furthermore, molecular dynamics (MD) simulations demonstrated that Thr416 and Glu418 of GIVA cPLA₂ contribute significantly to accommodating the hydrophilic head groups of PI and PI(4)P, which could explain some selectivity for PI and PI(4)P. These results indicated that GIVA cPLA₂ can accommodate PI and PI(4)P in its active site and hydrolyze them, suggesting that the GIVA cPLA₂ may best account for the PI and PIP hydrolysis in living cells.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159527"},"PeriodicalIF":3.9,"publicationDate":"2024-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000775/pdfft?md5=23d286a293fc0a12ab4dc508fd26a0b7&pid=1-s2.0-S1388198124000775-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased obesogenic action of palmitic acid during early stage of adipogenesis","authors":"Ewa Stanek ,&nbsp;Krzysztof Czamara ,&nbsp;Agnieszka Kaczor","doi":"10.1016/j.bbalip.2024.159525","DOIUrl":"10.1016/j.bbalip.2024.159525","url":null,"abstract":"<div><p>The functional differences between preadipocytes and fully differentiated mature adipocytes derived from stromal vascular fraction stem cells, as well as primary adipocytes have been analysed by evaluating their response to the obesogenic factor (a saturated fatty acid) and TNF-triggered inflammation. The analysis of single adipocytes shows that the saturated fatty acid (palmitic acid) accumulation is accompanied by inflammation and considerably dependent on the stage of the adipogenesis. In particular, preadipocytes show the exceptional potential for palmitic acid uptake resulting in their hypertrophy and the elevated cellular expression of the inflammation marker (ICAM-1). Our research provides new information on the impact of obesogenic factors on preadipocytes that is important in the light of childhood obesity prevention.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159525"},"PeriodicalIF":4.8,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000751/pdfft?md5=94478df13680f623ff6081e27a983da1&pid=1-s2.0-S1388198124000751-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver phospholipid fatty acid composition in response to chronic high-fat diets","authors":"Tamara Popović ,&nbsp;Aleksandra Nenadović ,&nbsp;Anica Stanković ,&nbsp;Jasmina Debeljak Martačić ,&nbsp;Slavica Ranković ,&nbsp;Sanjin Kovačević ,&nbsp;Jelena Nešović Ostojić ,&nbsp;Andjelija Ilić ,&nbsp;Jelena Milašin ,&nbsp;Silvio De Luka ,&nbsp;Alexander M. Trbovichch","doi":"10.1016/j.bbalip.2024.159526","DOIUrl":"10.1016/j.bbalip.2024.159526","url":null,"abstract":"<div><p>Liver phospholipid fatty acid composition depends on the dietary lipid intake and the efficiency of hepatic enzymatic activity. Our study aimed to simultaneously investigate the liver phospholipid fatty acid composition in response to chronic linseed, palm, or sunflower oil diets. We used adult female C57/BL6 mice and randomly divided them into control and three groups treated with 25 % dietary oils. Prior to treatment, we analyzed the fatty acid profiles in dietary oils and hepatocytes and, after 100 days, the fatty acid composition in the liver using gas-liquid chromatography. Linseed oil treatment elevated alpha-linolenic, eicosapentaenoic, and docosapentaenoic acids and reduced arachidonic and docosatetraenoic acids, consequently lowering the n-6/n-3 ratio. Palm oil treatment increased linoleic acid and decreased docosahexaenoic acid, contributing to an elevated n-6/n-3 ratio. Sunflower oil treatment elevated total monounsaturated fatty acids by increasing palmitoleic, oleic, and vaccenic acids. The estimated activity of Δ9 desaturase was significantly elevated in the sunflower oil group, while Δ5 desaturase was the highest, and Δ6 desaturase was the lowest after the linseed oil diet. Our findings demonstrate that chronic consumption of linseed, palm, or sunflower oil alters the distribution of liver phospholipid fatty acids differently. Sunflower oil diet elevated total monounsaturated fatty acids, proposing potential benefits for liver tissue health. Considering these outcomes, a substantial recommendation emerges to elevate linseed oil intake, recognized as the principal ALA source, thereby aiding in reducing the n-6/n-3 ratio. Moreover, modifying dietary habits to incorporate specific vegetable oils in daily consumption could substantially enhance overall health.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159526"},"PeriodicalIF":4.8,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid droplets control the negative effect of non-yeast sterols in membranes of Saccharomyces cerevisiae under hypoxic stress","authors":"Lívia Petrisková ,&nbsp;Marie Kodedová ,&nbsp;Mária Balážová ,&nbsp;Hana Sychrová ,&nbsp;Martin Valachovič","doi":"10.1016/j.bbalip.2024.159523","DOIUrl":"10.1016/j.bbalip.2024.159523","url":null,"abstract":"<div><p>The effectivity of utilization of exogenous sterols in the yeast <em>Saccharomyces cerevisiae</em> exposed to hypoxic stress is dependent on the sterol structure. The highly imported sterols include animal cholesterol or plant sitosterol, while ergosterol, typical of yeasts, is imported to a lesser extent. An elevated utilization of non-yeast sterols is associated with their high esterification and relocalization to lipid droplets (LDs). Here we present data showing that LDs and sterol esterification play a critical role in the regulation of the accumulation of non-yeast sterols in membranes. Failure to form LDs during anaerobic growth in media supplemented with cholesterol or sitosterol resulted in an extremely long lag phase, in contrast to normal growth in media with ergosterol or plant stigmasterol. Moreover, in <em>hem1</em>∆, which mimics anaerobiosis, neither cholesterol nor sitosterol supported the growth in an LD-less background. The incorporation of non-ergosterol sterols into the membranes affected fundamental membrane characteristics such as relative membrane potential, permeability, tolerance to osmotic stress and the formation of membrane domains. Our findings reveal that LDs assume an important role in scenarios wherein cells are dependent on the utilization of exogenous lipids, particularly under anoxia. Given the diverse lipid structures present in yeast niches, LDs fulfil a protective role, mitigating the risk of excessive accumulation of potentially toxic steroids and fatty acids in the membranes. Finally, we present a novel function for sterols in a model eukaryotic cell – alleviation of the lipotoxicity of unsaturated fatty acids.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159523"},"PeriodicalIF":4.8,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effects of fatty acid amide hydrolase inhibition in UVB-activated microglia","authors":"Veronica Carnicelli ,&nbsp;Noemi De Dominicis ,&nbsp;Lucia Scipioni ,&nbsp;Marina Fava ,&nbsp;Federico Fanti ,&nbsp;Benedetta Cinque ,&nbsp;Alessandro Leuti ,&nbsp;Clotilde Beatrice Angelucci ,&nbsp;Anna Rita Lizzi ,&nbsp;Roberto Giacominelli-Stuffler ,&nbsp;Vincenzo Flati ,&nbsp;Manuel Sergi ,&nbsp;Dario Compagnone ,&nbsp;Anna Maria Sardanelli ,&nbsp;Annamaria Tisi ,&nbsp;Sergio Oddi ,&nbsp;Mauro Maccarrone","doi":"10.1016/j.bbalip.2024.159524","DOIUrl":"10.1016/j.bbalip.2024.159524","url":null,"abstract":"<div><p>Neuroinflammation is a hallmark of several neurodegenerative disorders that has been extensively studied in recent years. Microglia, the primary immune cells of the central nervous system (CNS), are key players in this physiological process, demonstrating a remarkable adaptability in responding to various stimuli in the eye and the brain. Within the complex network of neuroinflammatory signals, the fatty acid <em>N</em>-ethanolamines, in particular <em>N</em>-arachidonylethanolamine (anandamide, AEA), emerged as crucial regulators of microglial activity under both physiological and pathological states. In this study, we interrogated for the first time the impact of the signaling of these bioactive lipids on microglial cell responses to a sub-lethal acute UVB radiation, a physical stressor responsible of microglia reactivity in either the retina or the brain. To this end, we developed an in vitro model using mouse microglial BV-2 cells. Upon 24 h of UVB exposure, BV-2 cells showed elevated oxidative stress markers and, cyclooxygenase (COX-2) expression, enhanced phagocytic and chemotactic activities, along with an altered immune profiling. Notably, UVB exposure led to a selective increase in expression and activity of fatty acid amide hydrolase (FAAH), the main enzyme responsible for degradation of fatty acid ethanolamides. Pharmacological FAAH inhibition via URB597 counteracted the effects of UVB exposure, decreasing tumor necrosis factor α (TNF-α) and nitric oxide (NO) release and reverting reactive oxidative species (ROS), interleukin-1β (IL-1β), and interleukin-10 (IL-10) levels to the control levels. Our findings support the potential of enhanced fatty acid amide signaling in mitigating UVB-induced cellular damage, paving the way to further exploration of these lipids in light-induced immune responses.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159524"},"PeriodicalIF":4.8,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S138819812400074X/pdfft?md5=a719f7b85c12fa8d0480943216d757a8&pid=1-s2.0-S138819812400074X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The lipid side of unfolded protein response","authors":"Wojciech Białek ,&nbsp;Anita Hryniewicz-Jankowska ,&nbsp;Paulina Czechowicz ,&nbsp;Jakub Sławski ,&nbsp;James F. Collawn ,&nbsp;Aleksander Czogalla ,&nbsp;Rafał Bartoszewski","doi":"10.1016/j.bbalip.2024.159515","DOIUrl":"10.1016/j.bbalip.2024.159515","url":null,"abstract":"<div><p>Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival. Lipid dysregulation is known to activate many aspects of the UPR, but the complexity of this crosstalk remains a major research barrier. ER lipid disequilibrium and lipotoxicity are known to be important contributors to numerous human pathologies, including insulin resistance, liver disease, cardiovascular diseases, neurodegenerative diseases, and cancer. Despite their medical significance and continuous research, however, the molecular mechanisms that modulate lipid synthesis during ER stress conditions, and their impact on cell fate decisions, remain poorly understood. Here we summarize the current view on crosstalk and connections between altered lipid metabolism, ER stress, and the UPR.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159515"},"PeriodicalIF":4.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000659/pdfft?md5=e64abfeac4129cb60c6ee6585091c8ae&pid=1-s2.0-S1388198124000659-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phospholipid isotope tracing suggests β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma","authors":"Chad VanSant-Webb ,&nbsp;Hayden K. Low ,&nbsp;Junko Kuramoto ,&nbsp;Claire E. Stanley ,&nbsp;Hantao Qiang ,&nbsp;Audrey Y. Su ,&nbsp;Alexis N. Ross ,&nbsp;Chad G. Cooper ,&nbsp;James E. Cox ,&nbsp;Scott A. Summers ,&nbsp;Kimberley J. Evason ,&nbsp;Gregory S. Ducker","doi":"10.1016/j.bbalip.2024.159514","DOIUrl":"10.1016/j.bbalip.2024.159514","url":null,"abstract":"<div><p>Activating mutations in the <em>CTNNB1</em> gene encoding β-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). Profound alterations in lipid metabolism, including increases in fatty acid oxidation and transformation of the phospholipidome, occur in HCC with <em>CTNNB1</em> mutations, but it is unclear what mechanisms give rise to these changes. We employed untargeted lipidomics and targeted isotope tracing to measure phospholipid synthesis activity in an inducible human liver cell line expressing mutant β-catenin, as well as in transgenic zebrafish with activated β-catenin-driven HCC. In both models, activated β-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid isotope tracing analysis in human cells revealed a reduction in phosphatidylcholine (PC) production rates as assayed by choline incorporation. We developed lipid isotope tracing analysis for zebrafish tumors and observed reductions in phosphatidylcholine synthesis by both the CDP-choline and PEMT pathways. The observed changes in the β-catenin-driven HCC phospholipidome suggest that zebrafish can recapitulate conserved features of HCC lipid metabolism and may serve as a model for identifying future HCC-specific lipid metabolic targets.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 6","pages":"Article 159514"},"PeriodicalIF":4.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic and lipidomic landscape of the infrapatellar fat pad and its clinical significance in knee osteoarthritis","authors":"Bizhi Tu ,&nbsp;Zheng Zhu ,&nbsp;Peizhi Lu ,&nbsp;Run Fang ,&nbsp;Cheng Peng ,&nbsp;Jun Tong ,&nbsp;Rende Ning","doi":"10.1016/j.bbalip.2024.159513","DOIUrl":"https://doi.org/10.1016/j.bbalip.2024.159513","url":null,"abstract":"<div><p>Osteoarthritis (OA) is a prevalent joint disease that can be exacerbated by lipid metabolism disorders. The intra-articular fat pad (IFP) has emerged as an active participant in the pathological changes of knee OA (KOA). However, the proteomic and lipidomic differences between IFP tissues from KOA and control individuals remain unclear. Samples of IFP were collected from individuals with and without OA (<em>n</em> = 6, n = 6). Subsequently, these samples underwent liquid chromatography/mass spectrometry-based label-free quantitative proteomic and lipidomic analysis to identify differentially expressed proteins (DEPs) and lipid metabolites (DELMs). The DEPs were further subjected to enrichment analysis, and hub DEPs were identified using multiple algorithms. Additionally, an OA diagnostic model was constructed based on the identified hub DEPs or DELMs. Furthermore, CIBERSORT was utilized to investigate the correlation between hub protein expression and immune-related modules in IFP of OA. Our results revealed the presence of 315 DEPs and eight DELMs in IFP of OA patients compared to the control group. Enrichment analysis of DEPs highlighted potential alterations in pathways related to coagulation, complement, fatty acid metabolism, and adipogenesis. The diagnostic model incorporating four hub DEPs (AUC = 0.861) or eight DELMs (AUC = 0.917) exhibited excellent clinical validity for diagnosing OA. Furthermore, the hub DEPs were found to be associated with immune dysfunction in IFP of OA. This study presents a distinct proteomic and lipidomic landscape of IFP between individuals with OA and those without. These findings provide valuable insights into the molecular changes associated with potential mechanisms underlying OA.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 6","pages":"Article 159513"},"PeriodicalIF":4.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT1/AMPK-mediated pathway: Ferulic acid from sugar beet pulp mitigating obesity-induced diabetes-linked complications and improving metabolic health","authors":"Sangeetha S.B. Singh,&nbsp;K. Neelakanteshwar Patil","doi":"10.1016/j.bbalip.2024.159511","DOIUrl":"10.1016/j.bbalip.2024.159511","url":null,"abstract":"<div><p>Obesity-induced type 2 diabetes (T2D) increases the risk of metabolic syndrome due to the high calorie intake. The role of sugar beet pulp (SBP) in T2D and the mechanism of its action remain unclear, though it is abundant in phenolics and has antioxidant activity. In this study, we isolated and purified ferulic acid from SBP, referred to as SBP-E, and studied the underlying molecular mechanisms in the regulation of glucose and lipid metabolism developing high glucose/high fat diet-induced diabetic models <em>in vitro</em> and <em>in vivo</em>. SBP-E showed no cytotoxicity and reduced the oxidative stress by increasing glutathione (GSH) in human liver (HepG2) and rat skeletal muscle (L6) cells. It also decreased body weight gain, food intake, fasting blood glucose levels (FBGL), glucose intolerance, hepatic steatosis, and lipid accumulation. Additionally, SBP-E decreased the oxidative stress and improved the antioxidant enzyme levels in high-fat diet (HFD)-induced T2D mice. Further, SBP-E reduced plasma and liver advanced glycation end products (AGEs), malondialdehyde (MDA), and pro-inflammatory cytokines, and increased anti-inflammatory cytokines in HFD-fed mice. Importantly, SBP-E significantly elevated AMPK, glucose transporter, SIRT1 activity, and Nrf2 expression and decreased ACC activity and SREBP1 levels in diabetic models. Collectively, our study results suggest that SBP-E treatment can improve obesity-induced T2D by regulating glucose and lipid metabolism via SIRT1/AMPK signalling and the AMPK/SREBP1/ACC1 pathway.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159511"},"PeriodicalIF":3.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sterol O-acyltransferase (SOAT/ACAT) activity is required to form cholesterol crystals in hepatocyte lipid droplets","authors":"Jordan A. Bairos ,&nbsp;Uche Njoku ,&nbsp;Maria Zafar ,&nbsp;May G. Akl ,&nbsp;Lei Li ,&nbsp;Gunes Parlakgul ,&nbsp;Ana Paula Arruda ,&nbsp;Scott B. Widenmaier","doi":"10.1016/j.bbalip.2024.159512","DOIUrl":"10.1016/j.bbalip.2024.159512","url":null,"abstract":"<div><h3>Objective</h3><p>Excess cholesterol storage can induce the formation of cholesterol crystals in hepatocyte lipid droplets. Such crystals distinguish metabolic dysfunction associated steatohepatitis (MASH) from simple steatosis and may underlie its pathogenesis by causing cell damage that triggers liver inflammation. The mechanism linking cholesterol excess to its crystallization in lipid droplets is unclear. As cholesteryl esters localize to and accumulate in lipid droplets more readily than unesterified free cholesterol, we investigated whether cholesterol esterification by sterol O-acyltransferase (SOAT), also known as acyl co-A cholesterol acyltransferase (ACAT), is required for hepatocyte lipid droplet crystal formation.</p></div><div><h3>Method</h3><p>Cholesterol crystals were measured in cholesterol loaded Hep3B hepatocytes, RAW264.7 macrophages, and mouse liver using polarizing light microscopy. We examined the effect of blocking SOAT activity on crystal formation and compared these results to features of cholesterol metabolism and the progression to intracellular crystal deposits.</p></div><div><h3>Results</h3><p>Cholesterol loading of Hep3B cells caused robust levels of lipid droplet localized crystal formation in a dose- and time-dependent manner. Co-treatment with SOAT inhibitors and genetic ablation of <em>SOAT1</em> blocked crystal formation. SOAT inhibitor also blocked crystal formation in low density lipoprotein (LDL) treated Hep3B cells, acetylated LDL treated RAW 264.7 macrophages, and in the liver of mice genetically predisposed to hepatic cholesterol overload and in mice with cholesterol enriched diet-induced MASH.</p></div><div><h3>Conclusion</h3><p>SOAT1-mediated esterification may underlie cholesterol crystals associated with MASH by concentrating it in lipid droplets. These findings imply that inhibiting hepatocyte SOAT1 may be able to alleviate cholesterol associated MASH. Moreover, that either a lipid droplet localized cholesteryl ester hydrolase is required for cholesterol crystal formation, or the crystals are composed of cholesteryl ester.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 6","pages":"Article 159512"},"PeriodicalIF":4.8,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000623/pdfft?md5=6ae20c50190534efe47379a32a0424e1&pid=1-s2.0-S1388198124000623-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}