Journal of Lipid Research最新文献

{"title":"Cholesterol affects the binding of proteins to phosphatidic acid without influencing its ionization properties.","authors":"Desmond Owusu Kwarteng, Alexander Wolf, Madisyn Langdon, Nawal Kassas, Nicolas Vitale, Edgar Eduard Kooijman","doi":"10.1016/j.jlr.2025.100749","DOIUrl":"10.1016/j.jlr.2025.100749","url":null,"abstract":"<p><p>Phosphatidic acid (PA) through its unique negatively charged phosphate headgroup binds to various proteins to modulate multiple cellular events. To perform such diverse signaling functions, the ionization and charge of PA's headgroup rely on the properties of vicinal membrane lipids and changes in cellular conditions. Cholesterol has conspicuous effects on lipid properties and membrane dynamics. In eukaryotic cells, its concentration increases along the secretory pathway, reaching its highest levels toward the plasma membrane. Moreover, membrane cholesterol levels are altered in certain diseases such as Alzheimer's disease, cancer, and in erythrocytes of hypercholesteremia patients. Hence, those changing levels of cholesterol could affect PA's charge and alter binding to effector protein. However, no study has investigated the direct impact of cholesterol on the ionization properties of PA. Here, we used ³¹P MAS NMR to explore the effects of increasing cholesterol concentrations on the chemical shifts and pKa2 of PA. We find that, while the chemical shifts of PA change significantly at high cholesterol concentrations, surprisingly, the pKa2 and charge of PA under these conditions are not modified. Furthermore, using in vitro lipid binding assays we found that higher cholesterol levels increased PA binding of the Spo20p PA sensor. Finally, in cellulo experiments demonstrated that depleting cholesterol from neurosecretory cells halts the recruitment of this sensor upon PA addition. Altogether, these data suggest that the intracellular cholesterol gradient may be an important regulator of proteins binding to PA and that disruption of those levels in certain pathologies may also affect PA binding to its target proteins and subsequent signaling pathways.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100749"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930147/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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 (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.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100752"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927683/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927713/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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+™ 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 and venous blood plasma in 10 male subjects using high-resolution mass spectrometry-based lipidomics. While there was substantial interindividual 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 and cardiolipins, 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":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932689/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957524/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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^hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their WT counterparts, WD-fed CYP7B1^hep.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 CYP7B1^hep.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 CYP7B1^hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1^hep.tg mouse liver accumulated 26HC and 25HC in response to WD. These data strongly suggested that 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":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954105/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"10.1016/j.jlr.2025.100762","url":null,"abstract":"<p><p>Intracellular cholesterol transport is essential for maintaining cellular cholesterol homeostasis. ATP-binding cassette A1 (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 remains 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 min 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":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957670/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multilayer regulation of postprandial triglyceride metabolism in response to acute cold exposure.","authors":"Yiliang Zhang, Shengyang Zhou, Runming Zhao, Chunyu Xiong, Yingzhen Huang, Minzhu Zhang, Yan Wang","doi":"10.1016/j.jlr.2025.100751","DOIUrl":"10.1016/j.jlr.2025.100751","url":null,"abstract":"<p><p>Triglyceride-rich lipoproteins carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multilayered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100751"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divergent effects of monomethyl branched-chain fatty acids on energy metabolism and insulin signaling in human myotubes.","authors":"Parmeshwar Bajirao Katare, Ragna H Tingstad, Sivar T Beajani, Jørgen Pasjkurov Indseth, Vibeke H Telle-Hansen, Mari C W Myhrstad, Arild C Rustan, Lars Eide, Oliwia Witczak, Vigdis Aas","doi":"10.1016/j.jlr.2025.100764","DOIUrl":"10.1016/j.jlr.2025.100764","url":null,"abstract":"<p><p>Branched-chain fatty acids (BCFAs) are predominantly saturated fatty acids with one or more methyl branches on the carbon chain, typically found in dairy products and measured in micromolar concentrations in human plasma. The biological function of BCFAs in humans remains ill-defined, but a relationship between circulating BCFAs and cardiometabolic health has been suggested. The objective of this study was to evaluate the impact of BCFAs on energy metabolism in human myotubes. The results revealed distinct effects of BCFAs. 12-Methyltetradecanoic acid (12-MTD) increased glucose uptake and glycogen synthesis, while 13-methyltetradecanoic acid (13-MTD), 14-methylhexadecanoic acid (14-MHD), and 15-methylhexadecanoic acid (15-MHD) increased oleic acid uptake and 13-MTD and 15-MHD oleic acid oxidation, indicating a more general stimulatory effect on fatty acid than glucose metabolism. Interestingly, the same BCFAs, 13-MTD, 14-MHD, and 15-MHD, appeared to reduce insulin-stimulated glycogen synthesis. Insulin-stimulated phosphorylation of IRS1 was not apparent after exposure to 12-MTD, 13-MTD, and 15-MHD, whereas insulin-stimulated phosphorylation of Akt was unchanged by BCFAs. Incorporation of [¹⁴C]leucine into lipids was affected, as 13-MTD increased the total lipid content, and 12-MTD altered the distribution of lipid classes. Metabolic flux analysis indicated that 14-MHD stimulated extracellular acidification. The effects of BCFAs might involve increased mRNA expression of pyruvate dehydrogenase kinase 4. In conclusion, the study demonstrates that different BCFAs have distinct effects on energy metabolism in myotubes, 12-MTD mainly affect glucose metabolism, while 13-MTD, 14-MHD, and 15-MHD modulated oleic acid metabolism. These data suggest that some BCFAs might have therapeutic applications by improving energy metabolism.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100764"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11982973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515888","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}