Pub Date : 2024-11-15DOI: 10.1016/j.bbalip.2024.159577
Wei Chen , Yuan Chen , Baoye Song , Lei Zhai , Geru Tao , Bingxiang Wang , Boyan Liu , Hao Wang , Cindy X. Zhang , Hong-mei Gu , Deling Yin , Shucun Qin , Da-wei Zhang
Surfeit locus protein 4 (SURF4) acts as a cargo receptor to mediate endoplasmic reticulum export of various cargos. We have shown that SURF4 is essential for secretion of hepatic very low-density lipoprotein and intestinal chylomicron. Knockdown of hepatic Surf4 also significantly reduces the development of atherosclerosis and liver fibrosis without causing overt liver damage. However, constitutive global Surf4 knockout results in embryonic lethality. To further understand the physiological role of SURF4, we generated tamoxifen-inducible global Surf4 knockout mice. We found that conditional knockout of Surf4 in adult mice (Surf4ig-ko) significantly reduced mouse body weight. Male and female Surf4ig-ko mice died approximately 30 and 50 days after tamoxifen administration, respectively. Triglyceride secretion and serum levels of total cholesterol, triglycerides, free fatty acids, apolipoprotein B-100, and apolipoprotein B-48 were significantly reduced in Surf4ig-ko mice compared with Surf4flox mice. Proteomics analysis of mouse serum samples revealed 308 proteins with significantly altered expression in Surf4ig-ko mice that have unique functions and are involved in various biological processes. In addition, Surf4ig-ko mice exhibited lipid accumulation in the intestine but not in the liver. However, in Surf4ig-ko mice, liver weight was significantly reduced, and serum transaminase activity was significantly increased, indicating liver damage. Therefore, SURF4 is essential for survival in adult mice, suggesting that the therapeutic use of SURF4 requires precise tissue/cell type-specific targeting.
{"title":"Inducible global knockout of surfeit locus protein 4 in adult mice results in hypolipidemia, intestinal lipid accumulation, liver injury, and increased mortality","authors":"Wei Chen , Yuan Chen , Baoye Song , Lei Zhai , Geru Tao , Bingxiang Wang , Boyan Liu , Hao Wang , Cindy X. Zhang , Hong-mei Gu , Deling Yin , Shucun Qin , Da-wei Zhang","doi":"10.1016/j.bbalip.2024.159577","DOIUrl":"10.1016/j.bbalip.2024.159577","url":null,"abstract":"<div><div>Surfeit locus protein 4 (SURF4) acts as a cargo receptor to mediate endoplasmic reticulum export of various cargos. We have shown that SURF4 is essential for secretion of hepatic very low-density lipoprotein and intestinal chylomicron. Knockdown of hepatic <em>Surf4</em> also significantly reduces the development of atherosclerosis and liver fibrosis without causing overt liver damage. However, constitutive global <em>Surf4</em> knockout results in embryonic lethality. To further understand the physiological role of SURF4, we generated tamoxifen-inducible global <em>Surf4</em> knockout mice. We found that conditional knockout of <em>Surf4</em> in adult mice (<em>Surf4</em><sup>ig-ko</sup>) significantly reduced mouse body weight. Male and female <em>Surf4</em><sup>ig-ko</sup> mice died approximately 30 and 50 days after tamoxifen administration, respectively. Triglyceride secretion and serum levels of total cholesterol, triglycerides, free fatty acids, apolipoprotein B-100, and apolipoprotein B-48 were significantly reduced in <em>Surf4</em><sup>ig-ko</sup> mice compared with <em>Surf4</em><sup>flox</sup> mice. Proteomics analysis of mouse serum samples revealed 308 proteins with significantly altered expression in <em>Surf4</em><sup>ig-ko</sup> mice that have unique functions and are involved in various biological processes. In addition, <em>Surf4</em><sup>ig-ko</sup> mice exhibited lipid accumulation in the intestine but not in the liver. However, in <em>Surf4</em><sup>ig-ko</sup> mice, liver weight was significantly reduced, and serum transaminase activity was significantly increased, indicating liver damage. Therefore, SURF4 is essential for survival in adult mice, suggesting that the therapeutic use of SURF4 requires precise tissue/cell type-specific targeting.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 2","pages":"Article 159577"},"PeriodicalIF":3.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643834","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}
Pub Date : 2024-11-14DOI: 10.1016/j.bbalip.2024.159579
Hanna Câmara da Justa , Antonielle Beatriz Baldissera , Mariana Izabele Machado , Samira Hajjar Souza , Nayanne Louise Costacurta Polli , Marianna Boia-Ferreira , Pedro Henrique de Caires Schluga , Lucelia Donatti , Ana Carolina M. Wille , João Carlos Minozzo , Luiza Helena Gremski , Silvio S. Veiga
Members of the phospholipase D (PLD) superfamily found in Loxosceles spider venoms are potent toxins with inflammatory and necrotizing activities. They degrade phospholipids in cell membranes, generating bioactive molecules that activate skin cells. These skin cells, in turn, activate leukocytes involved in dermonecrosis, characterized by aseptic coagulative necrosis. Although the literature has advanced in understanding the structure-function relationship, the cell biology resulting from the interactions of these molecules with cells remains poorly understood. In this study, we show that different cells exposed to recombinant PLDs bind these molecules to their plasma membrane, leading to the subsequent organization of extracellular microvesicles/ectosomes. The binding occurs as quickly as five minutes or less after exposure, increases over time, and eventually, the PLDs are expelled from the cell surface without generating cytotoxicity. PLDs are not endocytosed, nor do they spatially colocalize with acidic organelles in the intracellular environment. At least two regions of PLDs – the domain involved in magnesium ion coordination and the choline binding site – appear to play a role in cell surface binding and ectosome organization. However, the amino acids involved in catalysis do not participate in these events. The binding of these PLDs to the cell membrane, independent of catalytic activity, is sufficient to trigger intracellular signaling and enhance the expression of the pro-inflammatory IL-8 gene. These results are supported by the observation that isoforms of PLDs lacking catalytic activity induce an inflammatory response in vivo when injected into the skin of rabbits, without causing dermonecrosis. Our data indicate that these PLDs bind to the surface of target cells, promoting the organization of extracellular vesicles/ectosomes. Subsequently, these events activate pro-inflammatory genes and induce an inflammatory response in vivo. The binding to cells is not dependent on amino acids involved in catalysis but rather on amino acids involved in magnesium coordination. The binding of PLDs to the cell surface, formation of ectosomes, and activation of cells appear to initiate signals involved in inflammatory responses that can lead to dermonecrosis in accidents. This correlation is supported by experimental observations indicating that the events of toxin binding to cells, formation of microvesicles, and inflammatory responses observed both in vitro and in vivo are interconnected.
{"title":"Induction of ectosome formation by binding of phospholipases D from Loxosceles venoms to endothelial cell surface: Mechanism of interaction","authors":"Hanna Câmara da Justa , Antonielle Beatriz Baldissera , Mariana Izabele Machado , Samira Hajjar Souza , Nayanne Louise Costacurta Polli , Marianna Boia-Ferreira , Pedro Henrique de Caires Schluga , Lucelia Donatti , Ana Carolina M. Wille , João Carlos Minozzo , Luiza Helena Gremski , Silvio S. Veiga","doi":"10.1016/j.bbalip.2024.159579","DOIUrl":"10.1016/j.bbalip.2024.159579","url":null,"abstract":"<div><div>Members of the phospholipase D (PLD) superfamily found in <em>Loxosceles</em> spider venoms are potent toxins with inflammatory and necrotizing activities. They degrade phospholipids in cell membranes, generating bioactive molecules that activate skin cells. These skin cells, in turn, activate leukocytes involved in dermonecrosis, characterized by aseptic coagulative necrosis. Although the literature has advanced in understanding the structure-function relationship, the cell biology resulting from the interactions of these molecules with cells remains poorly understood. In this study, we show that different cells exposed to recombinant PLDs bind these molecules to their plasma membrane, leading to the subsequent organization of extracellular microvesicles/ectosomes. The binding occurs as quickly as five minutes or less after exposure, increases over time, and eventually, the PLDs are expelled from the cell surface without generating cytotoxicity. PLDs are not endocytosed, nor do they spatially colocalize with acidic organelles in the intracellular environment. At least two regions of PLDs – the domain involved in magnesium ion coordination and the choline binding site – appear to play a role in cell surface binding and ectosome organization. However, the amino acids involved in catalysis do not participate in these events. The binding of these PLDs to the cell membrane, independent of catalytic activity, is sufficient to trigger intracellular signaling and enhance the expression of the pro-inflammatory IL-8 gene. These results are supported by the observation that isoforms of PLDs lacking catalytic activity induce an inflammatory response <em>in vivo</em> when injected into the skin of rabbits, without causing dermonecrosis. Our data indicate that these PLDs bind to the surface of target cells, promoting the organization of extracellular vesicles/ectosomes. Subsequently, these events activate pro-inflammatory genes and induce an inflammatory response <em>in vivo</em>. The binding to cells is not dependent on amino acids involved in catalysis but rather on amino acids involved in magnesium coordination. The binding of PLDs to the cell surface, formation of ectosomes, and activation of cells appear to initiate signals involved in inflammatory responses that can lead to dermonecrosis in accidents. This correlation is supported by experimental observations indicating that the events of toxin binding to cells, formation of microvesicles, and inflammatory responses observed both <em>in vitro</em> and <em>in vivo</em> are interconnected.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 2","pages":"Article 159579"},"PeriodicalIF":3.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638333","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}
Pub Date : 2024-11-13DOI: 10.1016/j.bbalip.2024.159578
Tasvi Daya, Andrea Breytenbach, Liang Gu, Mandeep Kaur
Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.
{"title":"Cholesterol metabolism in pancreatic cancer and associated therapeutic strategies","authors":"Tasvi Daya, Andrea Breytenbach, Liang Gu, Mandeep Kaur","doi":"10.1016/j.bbalip.2024.159578","DOIUrl":"10.1016/j.bbalip.2024.159578","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 2","pages":"Article 159578"},"PeriodicalIF":3.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614034","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}
Pub Date : 2024-11-05DOI: 10.1016/j.bbalip.2024.159574
Marvin Leopold , Paola Berenice Mass-Sanchez , Marinela Krizanac , Paula Štancl , Rosa Karlić , Patricia Prabutzki , Victoria Parafianczuk , Jürgen Schiller , Anastasia Asimakopoulos , Kathrin M. Engel , Ralf Weiskirchen
The incidence of nonalcoholic fatty liver disease (NAFLD) has been steadily increasing in Western society in recent years and has been recognized as a risk factor for the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the progression from NAFLD to HCC are still unclear, despite the use of suitable mouse models. To identify the transcriptional and lipid profiles of livers from mice with NAFLD-HCC, we induced both NAFLD and NAFLD-HCC pathologies in C57BL/6J mice and performed RNA-sequencing (RNA-seq) and targeted lipidomic analysis. Our RNA-seq analysis revealed that the transcriptional signature of NAFLD in mice is characterized by changes in inflammatory response and fatty acid metabolism. Moreover, the signature of NAFLD-HCC is characterized by processes typically observed in cancer, such as epithelial to mesenchymal transition, angiogenesis and inflammatory responses. Furthermore, we found that the diet used in this study inhibited cholesterol synthesis in both models. The analysis of lipid composition also showed a significant impact of the provided diet. Therefore, our study supports the idea that a Western diet (WD) affects metabolic processes and hepatic lipid composition. Additionally, the combination of a WD with the administration of a carcinogen drives the progression from NAFLD to HCC.
{"title":"How the liver transcriptome and lipid composition influence the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma in a murine model","authors":"Marvin Leopold , Paola Berenice Mass-Sanchez , Marinela Krizanac , Paula Štancl , Rosa Karlić , Patricia Prabutzki , Victoria Parafianczuk , Jürgen Schiller , Anastasia Asimakopoulos , Kathrin M. Engel , Ralf Weiskirchen","doi":"10.1016/j.bbalip.2024.159574","DOIUrl":"10.1016/j.bbalip.2024.159574","url":null,"abstract":"<div><div>The incidence of nonalcoholic fatty liver disease (NAFLD) has been steadily increasing in Western society in recent years and has been recognized as a risk factor for the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the progression from NAFLD to HCC are still unclear, despite the use of suitable mouse models. To identify the transcriptional and lipid profiles of livers from mice with NAFLD-HCC, we induced both NAFLD and NAFLD-HCC pathologies in C57BL/6J mice and performed RNA-sequencing (RNA-seq) and targeted lipidomic analysis. Our RNA-seq analysis revealed that the transcriptional signature of NAFLD in mice is characterized by changes in inflammatory response and fatty acid metabolism. Moreover, the signature of NAFLD-HCC is characterized by processes typically observed in cancer, such as epithelial to mesenchymal transition, angiogenesis and inflammatory responses. Furthermore, we found that the diet used in this study inhibited cholesterol synthesis in both models. The analysis of lipid composition also showed a significant impact of the provided diet. Therefore, our study supports the idea that a Western diet (WD) affects metabolic processes and hepatic lipid composition. Additionally, the combination of a WD with the administration of a carcinogen drives the progression from NAFLD to HCC.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159574"},"PeriodicalIF":3.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603105","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}
Pub Date : 2024-11-01DOI: 10.1016/j.bbalip.2024.159576
Anne-Mari Mustonen , Marjo Malinen , Ville Paakinaho , Petri Lehenkari , Sanna Palosaari , Vesa Kärjä , Petteri Nieminen
Osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA) are inflammatory joint diseases that share partly similar symptoms but have different, inadequately understood pathogeneses. Adipose tissues, including intra-articular infrapatellar fat pad (IFP), may contribute to their development. Analysis of differentially expressed genes (DEGs) in IFPs could improve the diagnostics of these conditions and help to develop novel treatment strategies. The aim was to identify potentially crucial genes and pathways discriminating OA and RA IFPs using RNA sequencing analysis. We aimed to distinguish genetically distinct patient groups as a starting point for further translational studies with the eventual goal of personalized medicine. Samples were collected from arthritic knees during total knee arthroplasty of sex- and age-matched OA and seropositive RA patients (n = 5–6/group). Metabolic pathways of interest were investigated by whole transcriptome sequencing, and DEGs were analyzed with univariate tests, hierarchical clustering (HC), and pathway analyses. There was significant interindividual variation in mRNA expression patterns, but distinct subgroups of OA and RA patients emerged that reacted similarly to their disease states based on HC. Compared to OA, RA samples showed 703 genes to be upregulated and 691 genes to be downregulated. Signaling pathway analyses indicated that these DEGs had common pathways in lipid metabolism, fatty acid biosynthesis and degradation, adipocytokine and insulin signaling, inflammatory response, and extracellular matrix organization. The divergent mRNA expression profiles in RA and OA suggest contribution of IFP to the regulation of synovial inflammatory processes and articular cartilage degradation and could provide novel diagnostic and therapeutic targets.
骨关节炎（OA）和自身免疫驱动的类风湿性关节炎（RA）是炎症性关节疾病，它们有部分相似的症状，但病因不同，人们对其认识不足。包括关节内髌下脂肪垫（IFP）在内的脂肪组织可能是导致这两种疾病发生的原因之一。对IFP中差异表达基因（DEGs）的分析可以改善这些疾病的诊断，并有助于开发新的治疗策略。我们的目的是利用 RNA 测序分析找出区分 OA 和 RA IFP 的潜在关键基因和通路。我们旨在区分不同基因的患者群体，以此为起点开展进一步的转化研究，最终实现个性化医疗的目标。样本采集自性别和年龄匹配的 OA 和血清阳性 RA 患者（5-6 人/组）在全膝关节置换术中的关节炎膝关节。通过全转录组测序研究了感兴趣的代谢通路，并通过单变量检验、层次聚类（HC）和通路分析对DEGs进行了分析。mRNA表达模式存在明显的个体差异，但OA和RA患者出现了不同的亚组，根据HC，这些亚组对其疾病状态的反应相似。与 OA 相比，RA 样本中有 703 个基因上调，691 个基因下调。信号通路分析表明，这些DEGs在脂质代谢、脂肪酸生物合成和降解、脂肪细胞因子和胰岛素信号转导、炎症反应和细胞外基质组织中具有共同的通路。RA和OA中不同的mRNA表达谱表明，IFP对滑膜炎症过程和关节软骨降解的调控做出了贡献，并可能提供新的诊断和治疗靶点。
{"title":"RNA sequencing analysis reveals distinct gene expression patterns in infrapatellar fat pads of patients with end-stage osteoarthritis or rheumatoid arthritis","authors":"Anne-Mari Mustonen , Marjo Malinen , Ville Paakinaho , Petri Lehenkari , Sanna Palosaari , Vesa Kärjä , Petteri Nieminen","doi":"10.1016/j.bbalip.2024.159576","DOIUrl":"10.1016/j.bbalip.2024.159576","url":null,"abstract":"<div><div>Osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA) are inflammatory joint diseases that share partly similar symptoms but have different, inadequately understood pathogeneses. Adipose tissues, including intra-articular infrapatellar fat pad (IFP), may contribute to their development. Analysis of differentially expressed genes (DEGs) in IFPs could improve the diagnostics of these conditions and help to develop novel treatment strategies. The aim was to identify potentially crucial genes and pathways discriminating OA and RA IFPs using RNA sequencing analysis. We aimed to distinguish genetically distinct patient groups as a starting point for further translational studies with the eventual goal of personalized medicine. Samples were collected from arthritic knees during total knee arthroplasty of sex- and age-matched OA and seropositive RA patients (<em>n</em> = 5–6/group). Metabolic pathways of interest were investigated by whole transcriptome sequencing, and DEGs were analyzed with univariate tests, hierarchical clustering (HC), and pathway analyses. There was significant interindividual variation in mRNA expression patterns, but distinct subgroups of OA and RA patients emerged that reacted similarly to their disease states based on HC. Compared to OA, RA samples showed 703 genes to be upregulated and 691 genes to be downregulated. Signaling pathway analyses indicated that these DEGs had common pathways in lipid metabolism, fatty acid biosynthesis and degradation, adipocytokine and insulin signaling, inflammatory response, and extracellular matrix organization. The divergent mRNA expression profiles in RA and OA suggest contribution of IFP to the regulation of synovial inflammatory processes and articular cartilage degradation and could provide novel diagnostic and therapeutic targets.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159576"},"PeriodicalIF":3.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567655","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}
Pub Date : 2024-10-31DOI: 10.1016/j.bbalip.2024.159575
Ivan Bradić , Katharina B. Kuentzel , Anita Pirchheim , Silvia Rainer , Birgit Schwarz , Michael Trauner , Martin R. Larsen , Nemanja Vujić , Dagmar Kratky
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LALD). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal−/− mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal−/− mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.
{"title":"From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism","authors":"Ivan Bradić , Katharina B. Kuentzel , Anita Pirchheim , Silvia Rainer , Birgit Schwarz , Michael Trauner , Martin R. Larsen , Nemanja Vujić , Dagmar Kratky","doi":"10.1016/j.bbalip.2024.159575","DOIUrl":"10.1016/j.bbalip.2024.159575","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL<img>D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal−/− mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal−/− mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159575"},"PeriodicalIF":3.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563709","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}
Pub Date : 2024-10-28DOI: 10.1016/j.bbalip.2024.159573
Daphne Siciliani , Bente Ruyter , Guro Løkka , Kirsti Elisabeth Præsteng , Matteo Minghetti , Trond M. Kortner
Choline is now recognized as an essential nutrient to ensure lipid transport in Atlantic salmon. Its deficiency leads to excessive lipid accumulation in the enterocytes, a condition known as steatosis. The knowledge of lipid metabolism and steatosis in fish remains limited, motivating the use of in vitro intestinal models to perform deeper explorations. This study aimed to create an in vitro steatosis model using RTdi-MI, a new cell line derived from the distal intestine of rainbow trout. Cells were exposed to varying oleic acid (OA) concentrations over different time points (24 h, 72 h, and 168 h). Results indicated that the increasing OA concentration enhanced intracellular lipid droplet formation. Quantitative lipid analysis confirmed OA accumulation, which intensified with prolonged exposure and increased OA dose. Moreover, all cells, including controls, exhibited fatty acid metabolic activity. Such outcome was confirmed by light and fluorescence microscopy. Additionally, RTdi-MI cells expressed genes involved in lipid metabolism and synthesis similar to in vivo conditions. Collectively, our findings demonstrate the ability of RTdi-MI cells to accumulate OA in intracellular lipid droplets and mirror in vivo steatosis conditions, offering a new tool for exploring fish intestinal lipid metabolism.
胆碱是目前公认的确保大西洋鲑脂质运输的必需营养素。缺乏胆碱会导致肠细胞中脂质过度积累，这种情况被称为脂肪变性。对鱼类脂质代谢和脂肪变性的了解仍然有限，这促使人们使用体外肠道模型进行更深入的探索。本研究旨在利用 RTdi-MI（一种源自虹鳟鱼远端肠道的新细胞系）创建体外脂肪变性模型。细胞在不同的时间点（24 小时、72 小时和 168 小时）暴露于不同浓度的油酸（OA）中。结果表明，OA 浓度的增加会促进细胞内脂滴的形成。定量脂质分析证实了 OA 的积累，这种积累随着暴露时间的延长和 OA 剂量的增加而加剧。此外，包括对照组在内的所有细胞都表现出脂肪酸代谢活性。光镜和荧光显微镜证实了这一结果。此外，RTdi-MI 细胞表达的参与脂质代谢和合成的基因与体内情况类似。总之，我们的研究结果表明 RTdii-MI 细胞能够在细胞内脂滴中积累 OA，并反映体内脂肪变性的情况，为探索鱼类肠道脂质代谢提供了一种新工具。
{"title":"A fish intestinal in vitro model for investigation of lipid metabolism and steatosis","authors":"Daphne Siciliani , Bente Ruyter , Guro Løkka , Kirsti Elisabeth Præsteng , Matteo Minghetti , Trond M. Kortner","doi":"10.1016/j.bbalip.2024.159573","DOIUrl":"10.1016/j.bbalip.2024.159573","url":null,"abstract":"<div><div>Choline is now recognized as an essential nutrient to ensure lipid transport in Atlantic salmon. Its deficiency leads to excessive lipid accumulation in the enterocytes, a condition known as steatosis. The knowledge of lipid metabolism and steatosis in fish remains limited, motivating the use of in vitro intestinal models to perform deeper explorations. This study aimed to create an in vitro steatosis model using RTdi-MI, a new cell line derived from the distal intestine of rainbow trout. Cells were exposed to varying oleic acid (OA) concentrations over different time points (24 h, 72 h, and 168 h). Results indicated that the increasing OA concentration enhanced intracellular lipid droplet formation. Quantitative lipid analysis confirmed OA accumulation, which intensified with prolonged exposure and increased OA dose. Moreover, all cells, including controls, exhibited fatty acid metabolic activity. Such outcome was confirmed by light and fluorescence microscopy. Additionally, RTdi-MI cells expressed genes involved in lipid metabolism and synthesis similar to in vivo conditions. Collectively, our findings demonstrate the ability of RTdi-MI cells to accumulate OA in intracellular lipid droplets and mirror in vivo steatosis conditions, offering a new tool for exploring fish intestinal lipid metabolism.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159573"},"PeriodicalIF":3.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567651","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}
Pub Date : 2024-10-23DOI: 10.1016/j.bbalip.2024.159570
Suwen Chen , Haifei Lu , Guoliang Yin , Xin Zhang , Decheng Meng , Wenfei Yu , Linya Wang , Hongshuai Liu , Fengxia Zhang
Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.
{"title":"Hesperitin prevents non-alcoholic steatohepatitis by modulating mitochondrial dynamics and mitophagy via the AMPKα-Drp1/PINK1-Parkin signaling pathway","authors":"Suwen Chen , Haifei Lu , Guoliang Yin , Xin Zhang , Decheng Meng , Wenfei Yu , Linya Wang , Hongshuai Liu , Fengxia Zhang","doi":"10.1016/j.bbalip.2024.159570","DOIUrl":"10.1016/j.bbalip.2024.159570","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159570"},"PeriodicalIF":3.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493928","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}
Pub Date : 2024-10-19DOI: 10.1016/j.bbalip.2024.159571
Gundega Stelfa , Anna Miteniece , Baiba Svalbe , Edijs Vavers , Marina Makrecka-Kuka , Einars Kupats , Liga Kunrade , Vadims Parfejevs , Una Riekstina , Maija Dambrova , Liga Zvejniece
The sigma-1 receptor (S1R) is involved in intracellular lipid synthesis and transport. Recent studies have shown that its genetic inactivation impairs adipogenic differentiation in vitro. This study investigated the role of S1R in adipose tissue physiology and metabolic health using adult and old WT and S1R KO mice.
Visceral fat mass was increased in adult, but not old S1R-KO male mice compared to that of WT mice, despite having similar body weights, food intake, and energy expenditure. The average adipocyte size was 64 % larger in adult KO mice than in adult WT mice. Adult S1R-KO mice showed reduced plasma dehydroepiandrosterone sulfate (DHEA-S) and elevated fasting plasma leptin concentrations. Lipidomic analysis revealed alterations in plasma metabolite concentrations, particularly reduced levels of sphingomyelins, ceramides, phosphatidylcholines, lysophosphatidylcholines, and cholesteryl esters in adult mice. Decreased expression of Pparγ, Adipoq, and Atgl was detected in visceral white adipose tissue (vWAT) isolated from adult KO mice. Additionally, Fabp4 and Adipoq expression levels were significantly lower in KO adipose-derived stromal cells than in WT adipose-derived stromal cells. A fivefold increase in the mitochondrial fatty acid oxidation rate and a 43 % increase in electron transfer coupling capacity were detected in adult S1R-KO vWAT.
In summary, our investigation revealed an age-dependent association between increased visceral adiposity and decreased plasma levels of DHEA-S in S1R-deficient male mice. These findings underscore the potential role of S1R in regulating metabolic processes in adipose tissue and suggest that DHEA-S is a potential mediator of adiposity changes in the absence of S1R.
{"title":"Age-dependent changes in visceral adiposity are associated with decreased plasma levels of DHEA-S in sigma-1 receptor knockout male mice","authors":"Gundega Stelfa , Anna Miteniece , Baiba Svalbe , Edijs Vavers , Marina Makrecka-Kuka , Einars Kupats , Liga Kunrade , Vadims Parfejevs , Una Riekstina , Maija Dambrova , Liga Zvejniece","doi":"10.1016/j.bbalip.2024.159571","DOIUrl":"10.1016/j.bbalip.2024.159571","url":null,"abstract":"<div><div>The sigma-1 receptor (S1R) is involved in intracellular lipid synthesis and transport. Recent studies have shown that its genetic inactivation impairs adipogenic differentiation in vitro. This study investigated the role of S1R in adipose tissue physiology and metabolic health using adult and old WT and S1R KO mice.</div><div>Visceral fat mass was increased in adult, but not old S1R-KO male mice compared to that of WT mice, despite having similar body weights, food intake, and energy expenditure. The average adipocyte size was 64 % larger in adult KO mice than in adult WT mice. Adult S1R-KO mice showed reduced plasma dehydroepiandrosterone sulfate (DHEA-S) and elevated fasting plasma leptin concentrations. Lipidomic analysis revealed alterations in plasma metabolite concentrations, particularly reduced levels of sphingomyelins, ceramides, phosphatidylcholines, lysophosphatidylcholines, and cholesteryl esters in adult mice. Decreased expression of <em>Pparγ</em>, <em>Adipoq</em>, and <em>Atgl</em> was detected in visceral white adipose tissue (vWAT) isolated from adult KO mice. Additionally, <em>Fabp4</em> and <em>Adipoq</em> expression levels were significantly lower in KO adipose-derived stromal cells than in WT adipose-derived stromal cells. A fivefold increase in the mitochondrial fatty acid oxidation rate and a 43 % increase in electron transfer coupling capacity were detected in adult S1R-KO vWAT.</div><div>In summary, our investigation revealed an age-dependent association between increased visceral adiposity and decreased plasma levels of DHEA-S in S1R-deficient male mice. These findings underscore the potential role of S1R in regulating metabolic processes in adipose tissue and suggest that DHEA-S is a potential mediator of adiposity changes in the absence of S1R.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159571"},"PeriodicalIF":3.9,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457062","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}
Pub Date : 2024-10-18DOI: 10.1016/j.bbalip.2024.159572
Dominik Šťastný , Alena Balleková , Dana Tahotná , Lucia Pokorná , Roman Holič , Jana Humpolíčková , Peter Griač
Invasion of human red blood cells by the malaria parasite Plasmodium falciparum is followed by dramatic modifications of erythrocytes properties, including de novo formation of new membrane systems. Lipid transfer proteins from both the parasite and the host cell are most likely an important part of those membrane remodeling processes. Using bioinformatics and in silico structural analysis, we have identified five P. falciparum potential lipid transfer proteins containing cellular retinaldehyde binding – triple functional domain (CRAL-TRIO). Two of these proteins, C6KTD4, encoded by the PF3D7_0629900 gene and Q8II87, encoded by the PF3D7_1127600 gene, were studied in more detail. In vitro lipid transfer assays using recombinant C6KTD4 and Q8II87 confirmed that these proteins are indeed bona fide lipid transfer proteins. C6KTD4 transfers sterols, phosphatidylinositol 4,5 bisphosphate, and, to some degree, also phosphatidylcholine between two membrane compartments. Q8II87 possesses phosphatidylserine transfer activity in vitro. In the yeast model, the expression of P. falciparumQ8II87 protein partially complements the absence of Sec14p and its closest homologue, Sfh1p. C6KTD4 protein can substitute for the collective essential function of oxysterol-binding related proteins. According to published whole genome studies in P. falciparum, absence of C6KTD4 and Q8II87 proteins has severe consequences for parasite viability. Therefore, CRAL-TRIO lipid transfer proteins of P. falciparum are potential targets of novel antimalarials, in search for which the yeast model expressing these proteins could be a valuable tool.
{"title":"Characterization of two Plasmodium falciparum lipid transfer proteins of the Sec14/CRAL-TRIO family","authors":"Dominik Šťastný , Alena Balleková , Dana Tahotná , Lucia Pokorná , Roman Holič , Jana Humpolíčková , Peter Griač","doi":"10.1016/j.bbalip.2024.159572","DOIUrl":"10.1016/j.bbalip.2024.159572","url":null,"abstract":"<div><div>Invasion of human red blood cells by the malaria parasite <em>Plasmodium falciparum</em> is followed by dramatic modifications of erythrocytes properties, including <em>de novo</em> formation of new membrane systems. Lipid transfer proteins from both the parasite and the host cell are most likely an important part of those membrane remodeling processes. Using bioinformatics and <em>in silico</em> structural analysis, we have identified five <em>P. falciparum</em> potential lipid transfer proteins containing cellular retinaldehyde binding – triple functional domain (CRAL-TRIO). Two of these proteins, <span><span>C6KTD4</span><svg><path></path></svg></span>, encoded by the PF3D7_0629900 gene and <span><span>Q8II87</span><svg><path></path></svg></span>, encoded by the PF3D7_1127600 gene, were studied in more detail. <em>In vitro</em> lipid transfer assays using recombinant <span><span>C6KTD4</span><svg><path></path></svg></span> and <span><span>Q8II87</span><svg><path></path></svg></span> confirmed that these proteins are indeed <em>bona fide</em> lipid transfer proteins. <span><span>C6KTD4</span><svg><path></path></svg></span> transfers sterols, phosphatidylinositol 4,5 bisphosphate, and, to some degree, also phosphatidylcholine between two membrane compartments. <span><span>Q8II87</span><svg><path></path></svg></span> possesses phosphatidylserine transfer activity <em>in vitro</em>. In the yeast model, the expression of <em>P. falciparum</em> <span><span>Q8II87</span><svg><path></path></svg></span> protein partially complements the absence of Sec14p and its closest homologue, Sfh1p. <span><span>C6KTD4</span><svg><path></path></svg></span> protein can substitute for the collective essential function of oxysterol-binding related proteins. According to published whole genome studies in <em>P. falciparum</em>, absence of <span><span>C6KTD4</span><svg><path></path></svg></span> and <span><span>Q8II87</span><svg><path></path></svg></span> proteins has severe consequences for parasite viability. Therefore, CRAL-TRIO lipid transfer proteins of <em>P. falciparum</em> are potential targets of novel antimalarials, in search for which the yeast model expressing these proteins could be a valuable tool.</div></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1870 1","pages":"Article 159572"},"PeriodicalIF":3.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457063","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}
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