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Foamy monocytes and atherogenesis in mice with combined hyperlipidemia and effects of antisense knockdown of apoCIII.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-21 DOI: 10.1016/j.jlr.2025.100763
Xueying Peng, Zeqin Lian, Veronica O'Brien, Jing Xiao, Benjamin A Litchfield, Xiao-Yuan Dai Perrard, Lu Xu, Jing Ni, Aparna Mukherjee, Timothy Simmons, Henry Dong, Adam E Mullick, Rosanne Crooke, Henry J Pownall, Scott I Simon, Christie M Ballantyne, Huaizhu Wu

Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr-/- mice (Ldlr-/-ApoCIIItg) fed western high-fat diet (WD). Tissue culture with THP1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins (TGRL) on monocytes. Ldlr-/-ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr-/- mice, Ldlr-/-ApoCIIItg mice fed WD had early and persistent increases in lipid accumulation within monocytes and enhanced atherosclerosis. Ldlr-/-ApoCIIItg mice vs Ldlr-/- mice had higher levels of CD11c, CD36, and cytokines in foamy monocytes, with increases in foamy monocyte adhesion to VCAM-1 and oxLDL uptake. Monocytes took up TGRL in vivo and in vitro and changed phenotypes. Foamy monocytes infiltrated into atherosclerotic lesions, and specific and sustained depletion of CD11c+ (foamy) monocytes profoundly reduced atherosclerosis in Ldlr-/-ApoCIIItg mice on WD. Treatment with apoCIII ASO lowered plasma TG and cholesterol levels, improved foamy monocyte phenotypes, and reduced atherosclerosis in Ldlr-/-ApoCIIItg mice. In conclusion, HTG in combined hyperlipidemia accelerates atherosclerosis, in part, by increasing foamy monocyte formation and infiltration into atherosclerotic plaques. Treatment with apoCIII ASO is a potential new therapy for improving monocyte phenotypes and reducing atherosclerosis in combined hyperlipidemia.

{"title":"Foamy monocytes and atherogenesis in mice with combined hyperlipidemia and effects of antisense knockdown of apoCIII.","authors":"Xueying Peng, Zeqin Lian, Veronica O'Brien, Jing Xiao, Benjamin A Litchfield, Xiao-Yuan Dai Perrard, Lu Xu, Jing Ni, Aparna Mukherjee, Timothy Simmons, Henry Dong, Adam E Mullick, Rosanne Crooke, Henry J Pownall, Scott I Simon, Christie M Ballantyne, Huaizhu Wu","doi":"10.1016/j.jlr.2025.100763","DOIUrl":"10.1016/j.jlr.2025.100763","url":null,"abstract":"<p><p>Hypertriglyceridemia (HTG), particularly in combined hyperlipidemia, increases risk for atherosclerotic cardiovascular disease, but the underlying mechanisms remain incompletely understood. We sought to determine contributions of circulating monocytes to atherosclerosis associated with HTG in combined hyperlipidemia, created by transgenic expression of human apoCIII in Ldlr<sup>-/-</sup> mice (Ldlr<sup>-/-</sup>ApoCIIItg) fed western high-fat diet (WD). Tissue culture with THP1 and primary human monocytes was used to examine effects of triglyceride (TG)-rich lipoproteins (TGRL) on monocytes. Ldlr<sup>-/-</sup>ApoCIIItg mice were also treated with apoCIII antisense oligonucleotide (ASO) and examined for foamy monocytes and atherosclerosis. Compared to Ldlr<sup>-/-</sup> mice, Ldlr<sup>-/-</sup>ApoCIIItg mice fed WD had early and persistent increases in lipid accumulation within monocytes and enhanced atherosclerosis. Ldlr<sup>-/-</sup>ApoCIIItg mice vs Ldlr<sup>-/-</sup> mice had higher levels of CD11c, CD36, and cytokines in foamy monocytes, with increases in foamy monocyte adhesion to VCAM-1 and oxLDL uptake. Monocytes took up TGRL in vivo and in vitro and changed phenotypes. Foamy monocytes infiltrated into atherosclerotic lesions, and specific and sustained depletion of CD11c<sup>+</sup> (foamy) monocytes profoundly reduced atherosclerosis in Ldlr<sup>-/-</sup>ApoCIIItg mice on WD. Treatment with apoCIII ASO lowered plasma TG and cholesterol levels, improved foamy monocyte phenotypes, and reduced atherosclerosis in Ldlr<sup>-/-</sup>ApoCIIItg mice. In conclusion, HTG in combined hyperlipidemia accelerates atherosclerosis, in part, by increasing foamy monocyte formation and infiltration into atherosclerotic plaques. Treatment with apoCIII ASO is a potential new therapy for improving monocyte phenotypes and reducing atherosclerosis in combined hyperlipidemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100763"},"PeriodicalIF":5.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483398","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
ABCA1-mediated nascent HDL formation is precisely regulated by the plasma membrane cholesterol.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-18 DOI: 10.1016/j.jlr.2025.100762
Fumihiko Ogasawara, Kazumitsu Ueda

Intracellular cholesterol transport is essential for maintaining cellular cholesterol homeostasis. ABCA1 continuously moves cholesterol from the inner leaflet to the outer leaflet of the plasma membrane (PM) to maintain low inner leaflet cholesterol levels. When PM inner leaflet cholesterol levels exceed ER cholesterol levels, which are maintained at approximately 5 mol% by the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP), Aster-A/GramD1a transports the excess cholesterol to the ER. Furthermore, ABCA1 removes excess PM cholesterol by promoting its efflux as nascent high-density lipoprotein (HDL) particles. Thus, cellular cholesterol homeostasis is maintained by the coordinated action of SCAP-SREBP, Aster-A/GramD1a, and ABCA1. While the regulation of SCAP-SREBP and Aster-A/GramD1a is well-understood, the mechanism governing ABCA1 activity remain less understood. In this study, we investigated the impact of PM cholesterol levels on ABCA1-mediated cholesterol and phosphatidylcholine (PC) efflux. Cells were treated with various concentrations of methyl-β-cyclodextrin (MβCD) or MβCD-cholesterol for 30 minutes to modulate PM cholesterol levels. We found that the initial velocities of both cholesterol and PC efflux were dependent solely on PM cholesterol levels, despite both being substrates for ABCA1. Intriguingly, when PM cholesterol levels dropped below 70% of the level observed in cells cultured in the presence of 10% FBS, both cholesterol and PC efflux ceased, even in the presence of abundant PC in the PM. Our findings suggest that ABCA1-mediated nascent HDL formation is precisely regulated to maintain optimal PM cholesterol levels.

{"title":"ABCA1-mediated nascent HDL formation is precisely regulated by the plasma membrane cholesterol.","authors":"Fumihiko Ogasawara, Kazumitsu Ueda","doi":"10.1016/j.jlr.2025.100762","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100762","url":null,"abstract":"<p><p>Intracellular cholesterol transport is essential for maintaining cellular cholesterol homeostasis. ABCA1 continuously moves cholesterol from the inner leaflet to the outer leaflet of the plasma membrane (PM) to maintain low inner leaflet cholesterol levels. When PM inner leaflet cholesterol levels exceed ER cholesterol levels, which are maintained at approximately 5 mol% by the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP), Aster-A/GramD1a transports the excess cholesterol to the ER. Furthermore, ABCA1 removes excess PM cholesterol by promoting its efflux as nascent high-density lipoprotein (HDL) particles. Thus, cellular cholesterol homeostasis is maintained by the coordinated action of SCAP-SREBP, Aster-A/GramD1a, and ABCA1. While the regulation of SCAP-SREBP and Aster-A/GramD1a is well-understood, the mechanism governing ABCA1 activity remain less understood. In this study, we investigated the impact of PM cholesterol levels on ABCA1-mediated cholesterol and phosphatidylcholine (PC) efflux. Cells were treated with various concentrations of methyl-β-cyclodextrin (MβCD) or MβCD-cholesterol for 30 minutes to modulate PM cholesterol levels. We found that the initial velocities of both cholesterol and PC efflux were dependent solely on PM cholesterol levels, despite both being substrates for ABCA1. Intriguingly, when PM cholesterol levels dropped below 70% of the level observed in cells cultured in the presence of 10% FBS, both cholesterol and PC efflux ceased, even in the presence of abundant PC in the PM. Our findings suggest that ABCA1-mediated nascent HDL formation is precisely regulated to maintain optimal PM cholesterol levels.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100762"},"PeriodicalIF":5.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468318","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
Distinct pathways for the absorption and metabolism of β-carotene and zeaxanthin in the mouse intestine.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-17 DOI: 10.1016/j.jlr.2025.100758
Sepalika Bandara, Aicha Saadane, Tong Shen, Daryna Yakovleva, Rakhee Banerjee, Yanqi Zhang, J Mark Brown, Johannes von Lintig

Carotenoids, essential nutrients for eye health, are absorbed in the intestine to support vitamin A homeostasis and provide cellular protection. This process involves the lipid transporters scavenger receptor class B type 1 (SR-B1, encoded by Scarb1 gene) and Niemann-Pick C1-Like 1 (NPC1L1), which load these dietary lipids into the plasma membrane of intestinal enterocytes. However, the precise contribution of these transporters to carotenoid absorption, the putative involvement of Aster proteins in their downstream movement, and the interactions with their metabolizing enzymes, β-carotene oxygenase 1 (BCO1) and β-carotene oxygenase 2 (BCO2), remain incompletely understood. Here, we investigated carotenoid metabolism in the mouse intestine using pharmacological and genetic approaches. We observed that ezetimibe, an NPC1L1 inhibitor, reduced zeaxanthin but did not affect β-carotene absorption. Aster-C, highly expressed in enterocytes, bound zeaxanthin in biochemical assays. In mice, Aster-C deficiency led to upregulation of Gramd1b (Aster-B) expression and increased zeaxanthin bioavailability. We further showed that BCO1 directly interacted with membranes to extract β-carotene for retinoid production, indicating that vitamin A production is Aster protein-independent. This observation is consistent with the finding that the intestine specific transcription factor ISX, the master regulator of vitamin A production, controlled Scarb1 and Bco1 expression but had no effect on Gramd1a, b, or c, encoding Aster proteins in intestinal enterocytes. Together, our study revealed distinct pathways for β-carotene and zeaxanthin absorption and metabolism, offering new insights into carotenoid bioavailability and potential strategies to optimize dietary carotenoid intake for improved eye health.

{"title":"Distinct pathways for the absorption and metabolism of β-carotene and zeaxanthin in the mouse intestine.","authors":"Sepalika Bandara, Aicha Saadane, Tong Shen, Daryna Yakovleva, Rakhee Banerjee, Yanqi Zhang, J Mark Brown, Johannes von Lintig","doi":"10.1016/j.jlr.2025.100758","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100758","url":null,"abstract":"<p><p>Carotenoids, essential nutrients for eye health, are absorbed in the intestine to support vitamin A homeostasis and provide cellular protection. This process involves the lipid transporters scavenger receptor class B type 1 (SR-B1, encoded by Scarb1 gene) and Niemann-Pick C1-Like 1 (NPC1L1), which load these dietary lipids into the plasma membrane of intestinal enterocytes. However, the precise contribution of these transporters to carotenoid absorption, the putative involvement of Aster proteins in their downstream movement, and the interactions with their metabolizing enzymes, β-carotene oxygenase 1 (BCO1) and β-carotene oxygenase 2 (BCO2), remain incompletely understood. Here, we investigated carotenoid metabolism in the mouse intestine using pharmacological and genetic approaches. We observed that ezetimibe, an NPC1L1 inhibitor, reduced zeaxanthin but did not affect β-carotene absorption. Aster-C, highly expressed in enterocytes, bound zeaxanthin in biochemical assays. In mice, Aster-C deficiency led to upregulation of Gramd1b (Aster-B) expression and increased zeaxanthin bioavailability. We further showed that BCO1 directly interacted with membranes to extract β-carotene for retinoid production, indicating that vitamin A production is Aster protein-independent. This observation is consistent with the finding that the intestine specific transcription factor ISX, the master regulator of vitamin A production, controlled Scarb1 and Bco1 expression but had no effect on Gramd1a, b, or c, encoding Aster proteins in intestinal enterocytes. Together, our study revealed distinct pathways for β-carotene and zeaxanthin absorption and metabolism, offering new insights into carotenoid bioavailability and potential strategies to optimize dietary carotenoid intake for improved eye health.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100758"},"PeriodicalIF":5.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458300","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
PI3KC2β depletion rescues endosomal trafficking defects in Mtm1 knockout skeletal muscle cells.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-12 DOI: 10.1016/j.jlr.2025.100756
Mélanie Mansat, Afi Oportune Kpotor, Anne Mazars, Gaëtan Chicanne, Bernard Payrastre, Julien Viaud

Phosphoinositides constitute a class of seven phospholipids found in cell membranes, regulating various cellular processes like trafficking and signaling. Mutations in their metabolizing enzymes are implicated in several pathologies, including X-linked myotubular myopathy, a severe myopathy caused by mutations in the MTM1 gene. MTM1 (myotubularin 1) acts as a phosphoinositide 3-phosphatase, targeting PI3P (phosphatidylinositol 3-phosphate) and phosphatidylinositol 3,5-bisphosphate, crucial for endolysosomal trafficking. Studies in X-linked myotubular myopathy animal models have demonstrated that loss of MTM1 results in PI3P accumulation in muscle. Moreover, inactivating the class II phosphoinositide 3-kinase beta rescues the pathological phenotype and decreases PI3P levels, suggesting that the normalization of PI3P levels could be responsible for that rescue mechanism. In this study, using an Mtm1-KO skeletal muscle cell line, we investigated the localization of the PI3P pool metabolized by MTM1 in endosomal compartments. Our findings reveal that MTM1 metabolizes a pool of PI3P on EEA1 (early endosome antigen 1)-positive endosomes, leading to impaired Rab4 recycling vesicle biogenesis in the absence of MTM1. Furthermore, depletion of class II phosphoinositide 3-kinase beta rescued Mtm1-KO cell phenotype, normalized PI3P level on EEA1-positive endosomes, and restored Rab4-positive vesicle biogenesis. These results indicate that MTM1 is critical for the homeostasis of endosomal trafficking, and that depletion of MTM1 potentially alters cargo recycling through Rab4-positive vesicle trafficking.

{"title":"PI3KC2β depletion rescues endosomal trafficking defects in Mtm1 knockout skeletal muscle cells.","authors":"Mélanie Mansat, Afi Oportune Kpotor, Anne Mazars, Gaëtan Chicanne, Bernard Payrastre, Julien Viaud","doi":"10.1016/j.jlr.2025.100756","DOIUrl":"10.1016/j.jlr.2025.100756","url":null,"abstract":"<p><p>Phosphoinositides constitute a class of seven phospholipids found in cell membranes, regulating various cellular processes like trafficking and signaling. Mutations in their metabolizing enzymes are implicated in several pathologies, including X-linked myotubular myopathy, a severe myopathy caused by mutations in the MTM1 gene. MTM1 (myotubularin 1) acts as a phosphoinositide 3-phosphatase, targeting PI3P (phosphatidylinositol 3-phosphate) and phosphatidylinositol 3,5-bisphosphate, crucial for endolysosomal trafficking. Studies in X-linked myotubular myopathy animal models have demonstrated that loss of MTM1 results in PI3P accumulation in muscle. Moreover, inactivating the class II phosphoinositide 3-kinase beta rescues the pathological phenotype and decreases PI3P levels, suggesting that the normalization of PI3P levels could be responsible for that rescue mechanism. In this study, using an Mtm1-KO skeletal muscle cell line, we investigated the localization of the PI3P pool metabolized by MTM1 in endosomal compartments. Our findings reveal that MTM1 metabolizes a pool of PI3P on EEA1 (early endosome antigen 1)-positive endosomes, leading to impaired Rab4 recycling vesicle biogenesis in the absence of MTM1. Furthermore, depletion of class II phosphoinositide 3-kinase beta rescued Mtm1-KO cell phenotype, normalized PI3P level on EEA1-positive endosomes, and restored Rab4-positive vesicle biogenesis. These results indicate that MTM1 is critical for the homeostasis of endosomal trafficking, and that depletion of MTM1 potentially alters cargo recycling through Rab4-positive vesicle trafficking.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100756"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425602","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
Comparison of the capillary and venous blood plasma lipidomes- validation of self-collected blood for plasma lipidomics.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-12 DOI: 10.1016/j.jlr.2025.100755
Ahsan Hameed, Mario G Ferruzzi, Colin D Kay, D Keith Williams, Elaheh Rahbar, Andrew J Morris

Venipuncture of the upper extremities is commonly used to collect blood for plasma lipidomics. However, self-administered blood collection devices such as the Tasso+TM system for capillary blood sampling and plasma separation are convenient and enable frequent sampling without a clinical blood draw. The purpose of this study is to validate Tasso+ sampling for plasma lipidomics by comparing the venous blood and Tasso+ sampled capillary blood plasma lipidomes. Lipids are proven or putative biomarkers of human health and disease and indicators of nutritional and toxicological status. Because exchange of blood components including lipids occurs in capillaries, the capillary and venous blood lipidomes might be different which could confound use of Tasso+ sampled blood as a surrogate for venous blood plasma. Here we compared the lipidomes of Tasso+ drawn capillary blood plasma to venous blood plasma in 10 male subjects using high-resolution mass spectrometry-based lipidomics. While there was substantial inter individual variability between lipidomes, comprehensive statistical approaches with cross validation and multiple testing adjustments showed no difference (adjusted p-value > 0.05) in lipid composition of the paired blood samples. A linear regression model with Spearman correlation analysis also showed a significant-to-near-perfect level (r = 0.95-0.99) of concordance between the samples. Aside from monoacylglycerols (MG) and cardiolipins (CL), every class of lipid was strongly correlated (r = 0.9-0.99) between paired venous and capillary blood plasma. In summary, the capillary and venous blood plasma lipidomes are essentially identical making self-administered collection of capillary blood a viable approach for clinical blood plasma lipidomics.

{"title":"Comparison of the capillary and venous blood plasma lipidomes- validation of self-collected blood for plasma lipidomics.","authors":"Ahsan Hameed, Mario G Ferruzzi, Colin D Kay, D Keith Williams, Elaheh Rahbar, Andrew J Morris","doi":"10.1016/j.jlr.2025.100755","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100755","url":null,"abstract":"<p><p>Venipuncture of the upper extremities is commonly used to collect blood for plasma lipidomics. However, self-administered blood collection devices such as the Tasso+<sup>TM</sup> system for capillary blood sampling and plasma separation are convenient and enable frequent sampling without a clinical blood draw. The purpose of this study is to validate Tasso+ sampling for plasma lipidomics by comparing the venous blood and Tasso+ sampled capillary blood plasma lipidomes. Lipids are proven or putative biomarkers of human health and disease and indicators of nutritional and toxicological status. Because exchange of blood components including lipids occurs in capillaries, the capillary and venous blood lipidomes might be different which could confound use of Tasso+ sampled blood as a surrogate for venous blood plasma. Here we compared the lipidomes of Tasso+ drawn capillary blood plasma to venous blood plasma in 10 male subjects using high-resolution mass spectrometry-based lipidomics. While there was substantial inter individual variability between lipidomes, comprehensive statistical approaches with cross validation and multiple testing adjustments showed no difference (adjusted p-value > 0.05) in lipid composition of the paired blood samples. A linear regression model with Spearman correlation analysis also showed a significant-to-near-perfect level (r = 0.95-0.99) of concordance between the samples. Aside from monoacylglycerols (MG) and cardiolipins (CL), every class of lipid was strongly correlated (r = 0.9-0.99) between paired venous and capillary blood plasma. In summary, the capillary and venous blood plasma lipidomes are essentially identical making self-administered collection of capillary blood a viable approach for clinical blood plasma lipidomics.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100755"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425600","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
Liver specific transgenic expression of CYP7B1 attenuates early Western diet-induced MASLD progression.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-12 DOI: 10.1016/j.jlr.2025.100757
Genta Kakiyama, Nanah Bai-Kamara, Daniel Rodriguez-Agudo, Hajime Takei, Kei Minowa, Michael Fuchs, Sudha Biddinger, Jolene J Windle, Mark A Subler, Tsuyoshi Murai, Mitsuyoshi Suzuki, Hiroshi Nittono, Arun Sanyal, William M Pandak

Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-Hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their wild type (WT) counterparts, WD-fed CYP7B1hep.tg mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1hep.tg mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation and immune system including retinol metabolism, arachidonic acid metabolism and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1hep.tg mouse liver accumulated 26HC and 25HC in response to WD. This data strongly suggested these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a "proof-of-concept" that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression.

{"title":"Liver specific transgenic expression of CYP7B1 attenuates early Western diet-induced MASLD progression.","authors":"Genta Kakiyama, Nanah Bai-Kamara, Daniel Rodriguez-Agudo, Hajime Takei, Kei Minowa, Michael Fuchs, Sudha Biddinger, Jolene J Windle, Mark A Subler, Tsuyoshi Murai, Mitsuyoshi Suzuki, Hiroshi Nittono, Arun Sanyal, William M Pandak","doi":"10.1016/j.jlr.2025.100757","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100757","url":null,"abstract":"<p><p>Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-Hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1<sup>hep.tg</sup>) overexpressing mice with ad libitum WD feeding. Unlike their wild type (WT) counterparts, WD-fed CYP7B1<sup>hep.tg</sup> mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1<sup>hep.tg</sup> mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation and immune system including retinol metabolism, arachidonic acid metabolism and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1<sup>hep.tg</sup> mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1<sup>hep.tg</sup> mouse liver accumulated 26HC and 25HC in response to WD. This data strongly suggested these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a \"proof-of-concept\" that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100757"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425601","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
Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity. 在肥胖症中,删除脂肪 FXR 会加剧代谢缺陷并诱导内源性大麻脂质--2-油酰基甘油。
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-10 DOI: 10.1016/j.jlr.2025.100754
Weinan Zhou, Sarith R Bandara, Kyungwon Ko, Oludemilade Akinrotimi, Diego Hernández-Saavedra, Emily Richter, Noah Brauer, Taylor J Woodward, Heather B Bradshaw, Cecilia Leal, Sayeepriyadarshini Anakk

The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high fat diet (HFD)-fed control mice. Moreover, upon high fat diet challenge, these effects are worsened in adipocyte-specific Fxr knockout (Ad-FxrKO) mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that either Faah inhibition or deletion leads to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels, which is associated with obesity-related phenotypes. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.

{"title":"Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity.","authors":"Weinan Zhou, Sarith R Bandara, Kyungwon Ko, Oludemilade Akinrotimi, Diego Hernández-Saavedra, Emily Richter, Noah Brauer, Taylor J Woodward, Heather B Bradshaw, Cecilia Leal, Sayeepriyadarshini Anakk","doi":"10.1016/j.jlr.2025.100754","DOIUrl":"https://doi.org/10.1016/j.jlr.2025.100754","url":null,"abstract":"<p><p>The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high fat diet (HFD)-fed control mice. Moreover, upon high fat diet challenge, these effects are worsened in adipocyte-specific Fxr knockout (Ad-FxrKO) mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that either Faah inhibition or deletion leads to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels, which is associated with obesity-related phenotypes. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100754"},"PeriodicalIF":5.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408738","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
A multi-ancestry genome-wide association study and evaluation of polygenic scores of LDL-C levels.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-03 DOI: 10.1016/j.jlr.2025.100752
Umm-Kulthum Ismail Umlai, Salman M Toor, Yasser A Al-Sarraj, Shaban Mohammed, Moza S H Al Hail, Ehsan Ullah, Khalid Kunji, Ayman El-Menyar, Mohammed Gomaa, Amin Jayyousi, Mohamad Saad, Nadeem Qureshi, Jassim M Al Suwaidi, Omar M E Albagha

The genetic determinants of low-density lipoprotein cholesterol (LDL-C) levels in blood have been predominantly explored in European populations and remain poorly understood in Middle Eastern populations. We investigated the genetic architecture of LDL-C variation in Qatar by conducting a genome-wide association study (GWAS) on serum LDL-C levels using whole genome sequencing data of 13,701 individuals (discovery; n = 5,939, replication; n = 7,762) from the population-based Qatar Biobank (QBB) cohort. We replicated 168 previously reported loci from the largest LDL-C GWAS by the Global Lipids Genetics Consortium (GLGC), with high correlation in allele frequencies (R2 = 0.77) and moderate correlation in effect sizes (Beta; R2 = 0.53). We also performed a multi-ancestry meta-analysis with the GLGC study using MR-MEGA (Meta-Regression of Multi-Ethnic Genetic Association) and identified one novel LDL-C-associated locus; rs10939663 (SLC2A9; genomic control-corrected P = 1.25 × 10-8). Lastly, we developed Qatari-specific polygenic score (PGS) panels and tested their performance against PGS derived from other ancestries. The multi-ancestry-derived PGS (PGS000888) performed best at predicting LDL-C levels, whilst the Qatari-derived PGS showed comparable performance. Overall, we report a novel gene associated with LDL-C levels, which may be explored further to decipher its potential role in the etiopathogenesis of cardiovascular diseases. Our findings also highlight the importance of population-based genetics in developing PGS for clinical utilization.

{"title":"A multi-ancestry genome-wide association study and evaluation of polygenic scores of LDL-C levels.","authors":"Umm-Kulthum Ismail Umlai, Salman M Toor, Yasser A Al-Sarraj, Shaban Mohammed, Moza S H Al Hail, Ehsan Ullah, Khalid Kunji, Ayman El-Menyar, Mohammed Gomaa, Amin Jayyousi, Mohamad Saad, Nadeem Qureshi, Jassim M Al Suwaidi, Omar M E Albagha","doi":"10.1016/j.jlr.2025.100752","DOIUrl":"10.1016/j.jlr.2025.100752","url":null,"abstract":"<p><p>The genetic determinants of low-density lipoprotein cholesterol (LDL-C) levels in blood have been predominantly explored in European populations and remain poorly understood in Middle Eastern populations. We investigated the genetic architecture of LDL-C variation in Qatar by conducting a genome-wide association study (GWAS) on serum LDL-C levels using whole genome sequencing data of 13,701 individuals (discovery; n = 5,939, replication; n = 7,762) from the population-based Qatar Biobank (QBB) cohort. We replicated 168 previously reported loci from the largest LDL-C GWAS by the Global Lipids Genetics Consortium (GLGC), with high correlation in allele frequencies (R<sup>2</sup> = 0.77) and moderate correlation in effect sizes (Beta; R<sup>2</sup> = 0.53). We also performed a multi-ancestry meta-analysis with the GLGC study using MR-MEGA (Meta-Regression of Multi-Ethnic Genetic Association) and identified one novel LDL-C-associated locus; rs10939663 (SLC2A9; genomic control-corrected P = 1.25 × 10<sup>-8</sup>). Lastly, we developed Qatari-specific polygenic score (PGS) panels and tested their performance against PGS derived from other ancestries. The multi-ancestry-derived PGS (PGS000888) performed best at predicting LDL-C levels, whilst the Qatari-derived PGS showed comparable performance. Overall, we report a novel gene associated with LDL-C levels, which may be explored further to decipher its potential role in the etiopathogenesis of cardiovascular diseases. Our findings also highlight the importance of population-based genetics in developing PGS for clinical utilization.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100752"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255870","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
Efficacy of a novel PCSK9 inhibitory peptide alone and with evinacumab in a mouse model of atherosclerosis.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-03 DOI: 10.1016/j.jlr.2025.100753
José A Inia, Anita van Nieuwkoop-van Straalen, J Wouter Jukema, Bidda Rolin, Ellen Marie Staarup, Christina K Mogensen, Hans M G Princen, Anita M van den Hoek

Atherosclerosis is the major cause of cardiovascular disease. This study evaluated the effect of lipid lowering using a novel peptide inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and a monoclonal antibody against angiopoietin-like 3 (evinacumab), either alone or in combination in APOE∗3-Leiden.CETP mice fed a Western diet. Effects on body weight, plasma lipids, atherosclerotic lesion size, severity, composition, and morphology were assessed. Treatment with PCSK9 inhibitory peptide significantly decreased both cholesterol and triglycerides (-69% and -68%, respectively). Similar reductions were seen in evinacumab-treated mice (-44% and -55%, respectively). The combination of evinacumab and PCSK9 inhibitory peptide lowered these levels to a larger extent than evinacumab alone (cholesterol: -74%; triglycerides: -81%). Reductions occurred in non-HDL-C without changes in HDL-C. Atherosclerotic lesion size was significantly reduced in all treatment groups compared to vehicle controls (evinacumab: -72%; PCSK9 inhibitory peptide: -97%; combination: -98%). Similarly, all interventions improved atherosclerotic lesion severity, with more undiseased segments and fewer severe lesions. Evaluation of the composition of severe atherosclerotic plaques revealed significant improvement in lesion stability in mice treated with both evinacumab and PCSK9 inhibitory peptide, attributable to decreased macrophage content and increased collagen content. Additionally, evaluation of lipid concentrations in cynomolgus monkeys revealed the beneficial effects of the PCSK9 inhibitory peptide on total cholesterol and LDL-C levels. Treatment with a novel PCSK9 inhibitory peptide alone or with evinacumab shows great potential to reduce and stabilize atherosclerotic lesions.

{"title":"Efficacy of a novel PCSK9 inhibitory peptide alone and with evinacumab in a mouse model of atherosclerosis.","authors":"José A Inia, Anita van Nieuwkoop-van Straalen, J Wouter Jukema, Bidda Rolin, Ellen Marie Staarup, Christina K Mogensen, Hans M G Princen, Anita M van den Hoek","doi":"10.1016/j.jlr.2025.100753","DOIUrl":"10.1016/j.jlr.2025.100753","url":null,"abstract":"<p><p>Atherosclerosis is the major cause of cardiovascular disease. This study evaluated the effect of lipid lowering using a novel peptide inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) and a monoclonal antibody against angiopoietin-like 3 (evinacumab), either alone or in combination in APOE∗3-Leiden.CETP mice fed a Western diet. Effects on body weight, plasma lipids, atherosclerotic lesion size, severity, composition, and morphology were assessed. Treatment with PCSK9 inhibitory peptide significantly decreased both cholesterol and triglycerides (-69% and -68%, respectively). Similar reductions were seen in evinacumab-treated mice (-44% and -55%, respectively). The combination of evinacumab and PCSK9 inhibitory peptide lowered these levels to a larger extent than evinacumab alone (cholesterol: -74%; triglycerides: -81%). Reductions occurred in non-HDL-C without changes in HDL-C. Atherosclerotic lesion size was significantly reduced in all treatment groups compared to vehicle controls (evinacumab: -72%; PCSK9 inhibitory peptide: -97%; combination: -98%). Similarly, all interventions improved atherosclerotic lesion severity, with more undiseased segments and fewer severe lesions. Evaluation of the composition of severe atherosclerotic plaques revealed significant improvement in lesion stability in mice treated with both evinacumab and PCSK9 inhibitory peptide, attributable to decreased macrophage content and increased collagen content. Additionally, evaluation of lipid concentrations in cynomolgus monkeys revealed the beneficial effects of the PCSK9 inhibitory peptide on total cholesterol and LDL-C levels. Treatment with a novel PCSK9 inhibitory peptide alone or with evinacumab shows great potential to reduce and stabilize atherosclerotic lesions.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100753"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255873","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
Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.
IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-01 Epub Date: 2025-01-21 DOI: 10.1016/j.jlr.2025.100746
Beibei Chen, Ruixia Bao, Jujie Pan, Zicheng Zhu, Qian Chen, Dan Wang, Yuzheng Wu, Haiyang Yu, Yi Zhang, Tao Wang

Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites upregulate 3-hydroxy-3-methylglutaryl-CoA. Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of 3-hydroxy-3-methylglutaryl-CoA by activating adenosine A2A receptor via the Srebp-2/Creb axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting adenosine A2A receptor. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.

{"title":"Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.","authors":"Beibei Chen, Ruixia Bao, Jujie Pan, Zicheng Zhu, Qian Chen, Dan Wang, Yuzheng Wu, Haiyang Yu, Yi Zhang, Tao Wang","doi":"10.1016/j.jlr.2025.100746","DOIUrl":"10.1016/j.jlr.2025.100746","url":null,"abstract":"<p><p>Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites upregulate 3-hydroxy-3-methylglutaryl-CoA. Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of 3-hydroxy-3-methylglutaryl-CoA by activating adenosine A2A receptor via the Srebp-2/Creb axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting adenosine A2A receptor. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100746"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Journal of Lipid Research
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