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

{"title":"Lipidome of Acinetobacter baumannii antibiotic persister cells","authors":"Delphine Vergoz ,&nbsp;Annick Schaumann ,&nbsp;Isabelle Schmitz ,&nbsp;Carlos Afonso ,&nbsp;Emmanuelle Dé ,&nbsp;Corinne Loutelier-Bourhis ,&nbsp;Stéphane Alexandre","doi":"10.1016/j.bbalip.2024.159539","DOIUrl":"10.1016/j.bbalip.2024.159539","url":null,"abstract":"<div><p>Persister cells constitute a bacterial subpopulation able to survive to high concentrations of antibiotics. This phenotype is temporary and reversible, and thus could be involved in the recurrence of infections and emergence of antibiotic resistance. To better understand how persister cells survive to such high antibiotic concentration, we examined changes in their lipid composition. We thus compared the lipidome of <em>Acinetobacter baumannii</em> ATCC 19606^T persister cells formed under ciprofloxacin treatment with the lipidome of control cells grown without antibiotic. Using matrix assisted laser desorption ionisation-Fourier transform ion cyclotron resonance mass spectrometry, we observed a higher abundance of short chains and secondary chains without hydroxylation for lipid A in persister cells. Using liquid chromatography-tandem mass spectrometry, we found that persister cells produced particular phosphatidylglycerols, as LPAGPE and PAGPE, but also lipids with particular acyl chains containing additional hydroxyl group or uncommon di-unsaturation on C18 and C16 acyl chains. In order to determine the impact of these multiple lipidome modifications on membrane fluidity, fluorescence anisotropy assays were performed. They showed an increase of rigidity for the membrane of persister cells, inducing likely a decrease membrane permeability to protect cells during dormancy. Finally, we highlighted that <em>A. baumannii</em> persister cells also produced particular wax esters, composed of two fatty acids and a fatty diol. These uncommon storage lipids are key metabolites allowing a rapid bacterial regrow when antibiotic pressure disappears. These overall changes in persister lipidome may constitute new therapeutic targets to combat these particular dormant cells.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159539"},"PeriodicalIF":3.9,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early activation of hepatic stellate cells induces rapid initiation of retinyl ester breakdown while maintaining lecithin:retinol acyltransferase (LRAT) activity","authors":"Maya W. Haaker,&nbsp;Vera Goossens,&nbsp;Nina A.N. Hoogland,&nbsp;Hidde van Doorne,&nbsp;Ziqiong Wang,&nbsp;Jeroen W.A. Jansen,&nbsp;Dora V. Kaloyanova,&nbsp;Chris H.A. van de Lest,&nbsp;Martin Houweling,&nbsp;A. Bas Vaandrager,&nbsp;J. Bernd Helms","doi":"10.1016/j.bbalip.2024.159540","DOIUrl":"10.1016/j.bbalip.2024.159540","url":null,"abstract":"<div><p>Lecithin:retinol acyltransferase (LRAT) is the main enzyme producing retinyl esters (REs) in quiescent hepatic stellate cells (HSCs). When cultured on stiff plastic culture plates, quiescent HSCs activate and lose their RE stores in a process similar to that in the liver following tissue damage, leading to fibrosis. Here we validated HSC cultures in soft gels to study RE metabolism in stable quiescent HSCs and investigated RE synthesis and breakdown in activating HSCs.</p><p>HSCs cultured in a soft gel maintained characteristics of quiescent HSCs, including the size, amount and composition of their characteristic large lipid droplets. Quiescent gel-cultured HSCs maintained high expression levels of <em>Lrat</em> and a RE storing phenotype with low levels of RE breakdown. Newly formed REs are highly enriched in retinyl palmitate (RP), similar to freshly isolated quiescent HSCs, which is associated with high LRAT activity. Comparison of these quiescent gel-cultured HSCs with activated plastic-cultured HSCs showed that although during early activation the total RE levels and RP-enrichment are reduced, levels of RE formation are maintained and mediated by LRAT. Loss of REs was caused by enhanced RE breakdown in activating HSCs. Upon prolonged culturing, activated HSCs have lost their LRAT activity and produce small amounts of REs by DGAT1. This study reveals unexpected dynamics in RE metabolism during early HSC activation, which might be important in liver disease as early stages are reversible. Soft gel cultures provide a promising model to study RE metabolism in quiescent HSCs, allowing detailed molecular investigations on the mechanisms for storage and release.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159540"},"PeriodicalIF":3.9,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000908/pdfft?md5=62a2e62b2ffedeed72c59c7bc898b487&pid=1-s2.0-S1388198124000908-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet","authors":"Jayne-Norah Ntambi ,&nbsp;Mugagga Kalyesubula ,&nbsp;Dylan Cootway ,&nbsp;Sarah A. Lewis ,&nbsp;Yar Xin Phang ,&nbsp;Zhaojin Liu ,&nbsp;Lucas M. O'Neill ,&nbsp;Lucas Lefers ,&nbsp;Hailey Huff ,&nbsp;Jacqueline Rose Miller ,&nbsp;Veronica Pegkou Christofi ,&nbsp;Ethan Anderson ,&nbsp;Ahmed Aljohani ,&nbsp;Francis Mutebi ,&nbsp;Mainak Dutta ,&nbsp;Andrew Patterson ,&nbsp;James M. Ntambi","doi":"10.1016/j.bbalip.2024.159538","DOIUrl":"10.1016/j.bbalip.2024.159538","url":null,"abstract":"<div><p>Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159538"},"PeriodicalIF":3.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidome profiling of neutrophil-derived extracellular vesicles unveils their contribution to the ensemble of synovial fluid-derived extracellular vesicles during joint inflammation","authors":"Laura Varela ,&nbsp;Sanne Mol ,&nbsp;Esther W. Taanman-Kueter ,&nbsp;Sarah E. Ryan ,&nbsp;Leonie S. Taams ,&nbsp;Esther de Jong ,&nbsp;P. René van Weeren ,&nbsp;Chris H.A. van de Lest ,&nbsp;Marca H.M. Wauben","doi":"10.1016/j.bbalip.2024.159534","DOIUrl":"10.1016/j.bbalip.2024.159534","url":null,"abstract":"<div><p>The molecular signature of cell-derived extracellular vesicles (EVs) from synovial fluid (SF) offers insights into the cells and molecular processes associated with joint disorders and can be exploited to define biomarkers. The EV-signature is determined by cargo molecules and the lesser-studied lipid bilayer. We here investigated the lipidome of SF-EVs in inflamed joints derived from Rheumatoid Arthritis (RA) and Spondyloarthritis (SpA) patients, two autoimmune-driven joint diseases, and compared these signatures to the lipid profile of equine SF-EVs obtained during induced acute synovitis. Since neutrophils are primary SF-infiltrating cells during these inflammatory joint diseases, we also analyzed how inflammatory stimuli alter the lipidomic profile of human and equine neutrophil-derived EVs (nEVs) in vitro and how these signatures relate to the lipidome signatures of SF-EVs from inflamed joints. We identified neutrophil stimulation intensity-dependent changes in the lipidomic profile of nEVs with elevated presence of dihexosylceramide (lactosylceramide), phosphatidylserine, and phosphatidylethanolamine ether-linked lipid classes in human nEVs upon full neutrophil activation. In horses, levels of monohexosylceramide (glucosylceramide) increased instead of dihexosylceramide, indicating species-specific differences. The lipid profiles of RA and SpA SF-EVs were relatively similar and showed a relative resemblance with stimulated human nEVs. Similarly, the lipidome of equine synovitis-derived SF-EVs closer resembled the one of stimulated equine nEVs. Hence, lipidome profiling can provide insights into the contribution of nEVs to the heterogeneous pool of SF-EVs, deepening our understanding of inflammatory joint diseases and revealing molecular changes in joint homeostasis, which can lead to the development of more precise disease diagnosis and treatment strategies.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159534"},"PeriodicalIF":3.9,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000842/pdfft?md5=b7018f50fdfe244672644a6d343ca60b&pid=1-s2.0-S1388198124000842-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein H deficiency exacerbates alcohol-induced liver injury via gut Dysbiosis and altered bile acid metabolism","authors":"Yaming Liu ,&nbsp;Tingting Li ,&nbsp;Jun Xu ,&nbsp;Shanshan Li ,&nbsp;Binbin Li ,&nbsp;Mohamad Elgozair","doi":"10.1016/j.bbalip.2024.159535","DOIUrl":"10.1016/j.bbalip.2024.159535","url":null,"abstract":"<div><h3>Background</h3><p>APOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear.</p></div><div><h3>Methods</h3><p>C57BL/6 WT and <em>ApoH</em>^−/− mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed.</p></div><div><h3>Results</h3><p><em>ApoH</em>^−/− mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting <em>de novo</em> lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed <em>ApoH</em>^−/− mice. The concentrations of CA, NorCA, and HCA in the liver were higher in <em>ApoH</em>^−/− mice on an ethanol diet compared to the control mice (<em>p</em> &lt; 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism.</p></div><div><h3>Conclusion</h3><p>APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159535"},"PeriodicalIF":3.9,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of AreA on lipid biosynthesis under different nitrogen sources and C/N ratios in the model oleaginous fungus Mucor circinelloides","authors":"Xiuwen Wang,&nbsp;Shaoqi Li,&nbsp;Shuxian Pang,&nbsp;Qing Liu,&nbsp;Yuanda Song","doi":"10.1016/j.bbalip.2024.159537","DOIUrl":"10.1016/j.bbalip.2024.159537","url":null,"abstract":"<div><p><em>Mucor circinelloides</em> has been exploited as model filamentous fungi for studies of genetic manipulation of lipogenesis. It is widely recognized that lipid accumulation is increased when there is a lack of nitrogen source in oleaginous microorganism. Nitrogen metabolism in filamentous fungi is a complex process that can be regulated by the global nitrogen regulator AreA. In this study, we cultivated the <em>areA</em>-knockout and -overexpression strains obtained in our previous study, using 20 different nitrogen sources. It emerged that the disruption of AreA in <em>M. circinelloides</em> reduced its sensitivity to nitrogen availability, resulting in increased lipid synthesis. Specially, the <em>areA</em>-knockout strain was unable to fully utilize many nitrogen sources but the ammonium and glutamate. We continued to investigate lipid production at different molar C/N ratios using glucose as sole carbon source and ammonium sulfate as sole nitrogen source, of which the high C/N ratios activate high lipid accumulation. By comparing the experimental results with transcriptional analysis, we were able to identify the optimal process conditions suitable for lipid accumulation and potential targets for future metabolic engineering.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159537"},"PeriodicalIF":3.9,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141728694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles as a hydrolytic platform of secreted phospholipase A2","authors":"Makoto Murakami","doi":"10.1016/j.bbalip.2024.159536","DOIUrl":"10.1016/j.bbalip.2024.159536","url":null,"abstract":"<div><p>Extracellular vesicles (EVs) represent small vesicles secreted from cells, including exosomes (40–150 nm in diameter), which are released via the multivesicular endosomal pathway, and microvesicles and ectosomes (100–1000 nm), which are produced by plasma membrane budding. Broadly, EVs also include vesicles generated from dying cells, such as apoptotic bodies (5–10 μm), as well as exomeres (&lt; 50 nm), which are very small, non-membranous nanoparticles. EVs play important roles in cell-to-cell signaling in various aspects of cancer, immunity, metabolism, and so on by transferring proteins, microRNAs (miRNAs), and metabolites as cargos from donor cells to recipient cells. Although lipids are one of the major components of EVs, they have long been recognized as merely the “wall” that partitions the lumen of the vesicle from the outside. However, it has recently become obvious that lipid composition of EVs influences their properties and functions, that EVs act as a carrier of a variety of lipid mediators, and that lipid mediators are produced in EV membranes by the hydrolytic action of secreted phospholipase A₂s (sPLA₂s). In this article, we will make an overview of the roles of lipids in EVs, with a particular focus on sPLA₂-driven mobilization of lipid mediators from EVs and its biological significance.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159536"},"PeriodicalIF":3.9,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1388198124000866/pdfft?md5=9285bd7d715886c2a587b588b34e29e7&pid=1-s2.0-S1388198124000866-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141728695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ilexgenin A inhibits lipid accumulation in macrophages and reduces the progression of atherosclerosis through PTPN2/ERK1/2/ABCA1 signalling pathway","authors":"Qinyi Zhou ,&nbsp;Yang Wang ,&nbsp;Yaqiong Cheng ,&nbsp;Jing Zhou ,&nbsp;Wang Liu ,&nbsp;Xiaofeng Ma ,&nbsp;Shilin Tang ,&nbsp;Shangshu Tang ,&nbsp;Chaoke Tang","doi":"10.1016/j.bbalip.2024.159533","DOIUrl":"10.1016/j.bbalip.2024.159533","url":null,"abstract":"<div><p>Macrophage lipid accumulation indicates a pathological change in atherosclerosis. Ilexgenin A (IA), a pentacyclic triterpenoid compound, plays a role in preventing inflammation, bacterial infection, and fatty liver and induces a potential anti-atherogenic effect. However, the anti-atherosclerotic mechanism remains unclear. The present study investigated the effects of IA on lipid accumulation in macrophage-derived foam cells and atherogenesis in apoE^−/− mice. Our results indicated that the expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) was up-regulated by IA, promoting cholesterol efflux and reducing lipid accumulation in macrophages, which may be regulated by the protein tyrosine phosphatase non-receptor type 2 (PTPN2)/ERK1/2 signalling pathway. IA attenuated the progression of atherosclerosis in high-fat diet-fed apoE^−/− mice. PTPN2 knockdown with siRNA or treatment with an ERK1/2 agonist (Ro 67–7476) impeded the effects of IA on ABCA1 upregulation and cholesterol efflux in macrophages. These results suggest that IA inhibits macrophage lipid accumulation and alleviates atherosclerosis progression via the PTPN2/ERK1/2 signalling pathway.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159533"},"PeriodicalIF":3.9,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of nonesterified fatty acids in cancer biology: Focus on tryptophan and related metabolism","authors":"","doi":"10.1016/j.bbalip.2024.159531","DOIUrl":"10.1016/j.bbalip.2024.159531","url":null,"abstract":"<div><p>Plasma nonesterified fatty acids (NEFA) are elevated in cancer, because of decreased albumin levels and of fatty acid oxidation, and increased fatty acid synthesis and lipolysis. Albumin depletion and NEFA elevation maximally release albumin-bound tryptophan (Trp) and increase its flux down the kynurenine pathway, leading to increased production of proinflammatory kynurenine metabolites, which tumors use to undermine T-cell function and achieve immune escape. Activation of the aryl hydrocarbon receptor by kynurenic acid promotes extrahepatic Trp degradation by indoleamine 2,3-dioxygenase and leads to upregulation of poly (ADP-ribose) polymerase, activation of which and also of SIRT1 (silent mating type information regulation 2 homolog 1) could lead to depletion of NAD⁺ and ATP, resulting in cell death. NEFA also modulate heme synthesis and degradation, changes in which impact homocysteine metabolism and production of reduced glutathione and hydrogen sulphide. The significance of the interactions between heme and homocysteine metabolism in cancer biology has received little attention. Targeting Trp disposition in cancer to prevent the NEFA effects is suggested.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159531"},"PeriodicalIF":3.9,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrator complex subunit 6 promotes hepatocellular steatosis via β-catenin-PPARγ axis","authors":"","doi":"10.1016/j.bbalip.2024.159532","DOIUrl":"10.1016/j.bbalip.2024.159532","url":null,"abstract":"<div><p>Hepatic adipogenesis has common mechanisms with adipocyte differentiation such as PPARγ involvement and the induction of adipose tissue-specific molecules. A previous report demonstrated that integrator complex subunit 6 (INTS6) is required for adipocyte differentiation. This study aimed to investigate INTS6 expression and its role in hepatic steatosis progression. The expression of INTS6 and PPARγ was examined in the liver of a mouse model of steatohepatitis and in paired liver biopsy samples from 11 patients with severe obesity and histologically proven metabolic dysfunction associated steatohepatitis (MASH) before and one year after bariatric surgery. To induce hepatocellular steatosis in vitro, an immortalized human hepatocyte cell line Hc3716 was treated with free fatty acids. In the steatohepatitis mouse model, we observed hepatic induction of INTS6, PPARγ, and adipocyte-specific genes. In contrast, β-catenin which negatively regulates PPARγ was reduced. Biopsied human livers demonstrated a strong positive correlation (r² = 0.8755) between INTS6 and PPARγ mRNA levels. After bariatric surgery, gene expressions of PPARγ, FABP4, and CD36 were mostly downregulated. In our in vitro experiments, we observed a concentration-dependent increase in Oil Red O staining in Hc3716 cells after treatment with the free fatty acids. Alongside this change, the expression of INTS6, PPARγ, and adipocyte-specific genes was induced. INTS6 knockdown using siRNA significantly suppressed cellular lipid accumulation together with induction of β-catenin and PPARγ downregulation. Collectively, INTS6 expression closely correlates with PPARγ. INTS6 suppression significantly reduced hepatocyte steatosis via β-catenin-PPARγ axis, indicating that INTS6 could be a novel therapeutic target for treating MASH.</p></div>","PeriodicalId":8815,"journal":{"name":"Biochimica et biophysica acta. Molecular and cell biology of lipids","volume":"1869 7","pages":"Article 159532"},"PeriodicalIF":3.9,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562571","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}