JCI insightPub Date : 2024-08-27DOI: 10.1172/jci.insight.179012
William J Melvin,Tyler M Bauer,Kevin D Magnum,Christopher O Audu,James Shadiow,Emily Barrett,Amrita Joshi,Jadie Y Moon,Rachel Bogel,Purba Mazumder,Sonya J Wolf,Steven Kunkel,Johann E Gudjonsson,Frank M Davis,Katherine A Gallagher
{"title":"The histone methyltransferase mixed-lineage-leukemia-1 drives T cell phenotype via notch signaling in diabetic tissue repair.","authors":"William J Melvin,Tyler M Bauer,Kevin D Magnum,Christopher O Audu,James Shadiow,Emily Barrett,Amrita Joshi,Jadie Y Moon,Rachel Bogel,Purba Mazumder,Sonya J Wolf,Steven Kunkel,Johann E Gudjonsson,Frank M Davis,Katherine A Gallagher","doi":"10.1172/jci.insight.179012","DOIUrl":"https://doi.org/10.1172/jci.insight.179012","url":null,"abstract":"Immune cell mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+T cells in normal or diabetic wound repair, however, the imbalance of CD4+TH17/Treg cells has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase MLL1 directly regulates the TH17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Further, we found that Notch receptor signaling regulates CD4+TH cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+T cells resulted in the loss of CD4+TH cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling were upregulated in wound CD4+TH cells, driving CD4+ T cells towards the TH17 cell phenotype. Treatment of diabetic wound CD4T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+TH17 cells and IL17A. This is the first study to identify the MLL1-mediated mechanisms responsible for regulating the TH17/Treg balance in normal and diabetic wounds and define the complex role of Notch signaling in CD4+T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+TH cells may decrease pathologic inflammation through regulation of CD4+T cell differentiation.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142188983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-27DOI: 10.1172/jci.insight.144448
Mariya B Shapiro, Tracy Ordonez, Shilpi Pandey, Eisa Mahyari, Kosiso Onwuzu, Jason Reed, Heather Sidener, Jeremy Smedley, Lois M Colgin, Amanda Johnson, Anne D Lewis, Benjamin Bimber, Jonah B Sacha, Ann J Hessell, Nancy L Haigwood
{"title":"Immune perturbation following SHIV infection is greater in newborn macaques than in infants.","authors":"Mariya B Shapiro, Tracy Ordonez, Shilpi Pandey, Eisa Mahyari, Kosiso Onwuzu, Jason Reed, Heather Sidener, Jeremy Smedley, Lois M Colgin, Amanda Johnson, Anne D Lewis, Benjamin Bimber, Jonah B Sacha, Ann J Hessell, Nancy L Haigwood","doi":"10.1172/jci.insight.144448","DOIUrl":"https://doi.org/10.1172/jci.insight.144448","url":null,"abstract":"<p><p>Transmission of HIV-1 to newborns and infants remains high, with 130,000 new infections in 2022 in resource poor settings. Half of HIV-infected newborns, if untreated, progress to disease and death within 2 years. While immunologic immaturity likely promotes pathogenesis and poor viral control, little is known about immune damage in newborns and infants. Here we examined pathologic, virologic, and immunologic outcomes in rhesus macaques exposed to pathogenic SHIV at 1-2 weeks, defined as newborns, or at 4 months of age, considered infants. Kinetics of plasma viremia and lymph node seeding DNA were indistinguishable in newborns and infants, but levels of viral DNA in gut and lymphoid tissues 6-10 weeks post-infection were significantly higher in newborns versus either infant or adult macques. Two of six newborns with the highest viral seeding required euthanasia at 25 days. We observed age-dependent alterations in leukocyte subsets and gene expression. Compared with infants, newborns had stronger skewing of monocytes and CD8+ T cells toward differentiated subsets and little evidence of type I interferon responses by transcriptomic analyses. Thus, SHIV infection reveals distinct immunological alterations in newborn and infant macaques. These studies lay the groundwork for understanding how immune maturation affects pathogenesis in pediatric HIV-1 infection.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-27DOI: 10.1172/jci.insight.168476
Pablo Fernández-Tussy, Magdalena P Cardelo, Hanming Zhang, Jonathan Sun, Nathan L Price, Nabil E Boutagy, Leigh Goedeke, Martí Cadena-Sandoval, Chrysovalantou E Xirouchaki, Wendy A Brown, Xiaoyong Yang, Oscar Pastor-Rojo, Rebecca A Haeusler, Anton M Bennett, Tony Tiganis, Yajaira Suárez, Carlos Fernández-Hernando
{"title":"miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression.","authors":"Pablo Fernández-Tussy, Magdalena P Cardelo, Hanming Zhang, Jonathan Sun, Nathan L Price, Nabil E Boutagy, Leigh Goedeke, Martí Cadena-Sandoval, Chrysovalantou E Xirouchaki, Wendy A Brown, Xiaoyong Yang, Oscar Pastor-Rojo, Rebecca A Haeusler, Anton M Bennett, Tony Tiganis, Yajaira Suárez, Carlos Fernández-Hernando","doi":"10.1172/jci.insight.168476","DOIUrl":"10.1172/jci.insight.168476","url":null,"abstract":"<p><p>The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-27DOI: 10.1172/jci.insight.179899
Anna E Kersh, Satish Sati, Jianhe Huang, Christina Murphy, Olivia C Ahart, Thomas H Leung
{"title":"CXCL9, CXCL10, and CCL19 synergistically recruit T-lymphocytes to skin in lichen planus.","authors":"Anna E Kersh, Satish Sati, Jianhe Huang, Christina Murphy, Olivia C Ahart, Thomas H Leung","doi":"10.1172/jci.insight.179899","DOIUrl":"https://doi.org/10.1172/jci.insight.179899","url":null,"abstract":"<p><p>Lichen planus (LP) is a chronic, debilitating, inflammatory disease of the skin and mucous membranes that affects 1% to 2% of Americans. Its molecular pathogenesis remains poorly understood, and there are no FDA-approved treatments. We performed single cell RNA sequencing on paired blood and skin samples (lesional and non-lesional tissue) from 7 LP patients. We discovered that LP keratinocytes and fibroblasts specifically secrete a combination of CXCL9, CXCL10, and CCL19 cytokines. Using an in vitro migration assay with primary human T cells, we demonstrated that CCL19 in combination with either cytokine synergistically enhanced recruitment of CD8 T cells, more than the sum of individual cytokines. Moreover, exhausted T cells in lesional LP skin secreted CXCL13, which along with CCL19 also enhanced recruitment of T cells, suggesting a feed-forward loop in LP. Finally, LP blood revealed decreased circulating naïve CD8 T cells compared to healthy volunteers, consistent with recruitment to skin. Molecular analysis of LP skin and blood samples increased our understanding of disease pathogenesis and identified CCL19 as a new therapeutic target for treatment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-27DOI: 10.1172/jci.insight.178719
Jerome M Karp, Aram S Modrek, Ravesanker Ezhilarasan, Ze-Yan Zhang, Yingwen Ding, Melanie Graciani, Ali Sahimi, Michele Silvestro, Ting Chen, Shuai Li, Kwok-Kin Wong, Bhama Ramkhelawon, Krishna Pl Bhat, Erik P Sulman
{"title":"Deconvolution of the tumor-educated platelet transcriptome reveals activated platelet and inflammatory cell transcript signatures.","authors":"Jerome M Karp, Aram S Modrek, Ravesanker Ezhilarasan, Ze-Yan Zhang, Yingwen Ding, Melanie Graciani, Ali Sahimi, Michele Silvestro, Ting Chen, Shuai Li, Kwok-Kin Wong, Bhama Ramkhelawon, Krishna Pl Bhat, Erik P Sulman","doi":"10.1172/jci.insight.178719","DOIUrl":"https://doi.org/10.1172/jci.insight.178719","url":null,"abstract":"<p><p>Tumor-educated platelets (TEPs) are a potential method of liquid biopsy for the diagnosis and monitoring of cancer. However, the mechanism underlying tumor education of platelets is not known, and transcripts associated with TEPs are often not tumor-associated transcripts. We demonstrated that direct tumor transfer of transcripts to circulating platelets is an unlikely source of the TEP signal. We used CDSeq, a latent Dirichlet allocation algorithm, to deconvolute the TEP signal in blood samples from patients with glioblastoma. We demonstrated that a substantial proportion of transcripts in the platelet transcriptome are derived from non-platelet cells, and the use of this algorithm allows the removal of contaminant transcripts. Furthermore, we used the results of this algorithm to demonstrate that TEPs represent a subset of more activated platelets, which also contain transcripts normally associated with non-platelet inflammatory cells, suggesting that these inflammatory cells, possibly in the tumor microenvironment, transfer transcripts to platelets that are then found in circulation. Our analysis suggests a useful and efficient method of processing TEP transcriptomic data to enable the isolation of a unique TEP signal associated with specific tumors.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"IL-27/Blimp-1 axis regulates the differentiation and function of Tim-3+ Tregs during early pregnancy.","authors":"Si-Jia Zhao, Xiao-Hui Hu, Xin-Xiu Lin, Yu-Jing Zhang, Jing Wang, Huan Wang, Guang-Shun Gong, Gil Mor, Ai-Hua Liao","doi":"10.1172/jci.insight.179233","DOIUrl":"10.1172/jci.insight.179233","url":null,"abstract":"<p><p>Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-22DOI: 10.1172/jci.insight.179876
Victoria Leroy, Denny Joseph Manual Kollareth, Zhenxiao Tu, Jeff Arni C Valisno, Makena Woolet-Stockton, Biplab K Saha, Amir M Emtiazjoo, Mindaugas Rackauskas, Lyle L Moldawer, Philip A Efron, Guoshuai Cai, Carl Atkinson, Gilbert R Upchurch, Ashish K Sharma
{"title":"MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant ischemia-reperfusion injury.","authors":"Victoria Leroy, Denny Joseph Manual Kollareth, Zhenxiao Tu, Jeff Arni C Valisno, Makena Woolet-Stockton, Biplab K Saha, Amir M Emtiazjoo, Mindaugas Rackauskas, Lyle L Moldawer, Philip A Efron, Guoshuai Cai, Carl Atkinson, Gilbert R Upchurch, Ashish K Sharma","doi":"10.1172/jci.insight.179876","DOIUrl":"10.1172/jci.insight.179876","url":null,"abstract":"<p><p>Lung transplantation (LTx) outcomes are impeded by ischemia-reperfusion injury (IRI) and subsequent chronic lung allograft dysfunction (CLAD). We examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis to facilitate resolution of lung IRI. Single-cell RNA sequencing of lung tissue and bronchoalveolar lavage (BAL) from post-LTx patients were analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), Cebpb-/- (MDSC-deficient), Mertk-/- or MerTK-CR (cleavage resistant) mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients was observed compared to healthy subjects. In the murine IRI model, significant increase in M-MDSCs, MerTK expression, efferocytosis and attenuation of lung dysfunction was observed in WT mice during injury resolution that was absent in Cebpb-/- and Mertk-/- mice. Adoptive transfer of M-MDSCs in Cebpb-/- mice significantly attenuated lung dysfunction and inflammation. Additionally, in a murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can substantially contribute to the resolution of post-LTx IRI.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-22DOI: 10.1172/jci.insight.179854
Rebecca Rosberg, Karolina I Smolag, Jonas Sjölund, Elinn Johansson, Christina Bergelin, Julia Wahldén, Vasiliki Pantazopoulou, Crister Ceberg, Kristian Pietras, Anna M Blom, Alexander Pietras
{"title":"Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment.","authors":"Rebecca Rosberg, Karolina I Smolag, Jonas Sjölund, Elinn Johansson, Christina Bergelin, Julia Wahldén, Vasiliki Pantazopoulou, Crister Ceberg, Kristian Pietras, Anna M Blom, Alexander Pietras","doi":"10.1172/jci.insight.179854","DOIUrl":"https://doi.org/10.1172/jci.insight.179854","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single cell, and spatially resolved transcriptomic data from human GBM patients. Complement component 3 (C3) and the receptor C3AR1 were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level-dependent increase in C3 and C3AR1 expression in response to hypoxia in several GBM and stromal cell types. C3a induced M2 polarization of cultured microglia and macrophages in a C3aR-dependent fashion. Targeting C3aR using the antagonist SB290157 prolonged survival of glioma bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM, and support a role of hypoxia-induced C3a-C3aR signaling as a contributor to glioma aggressiveness by regulating macrophage polarization.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-22DOI: 10.1172/jci.insight.181553
Xiaomin Liu, Yiliang Zhang, Bingqian Han, Lin Li, Ying Li, Yifan Ma, Shijia Kang, Quan Li, Lingkai Kong, Kun Huang, Bao-Liang Song, Yong Liu, Yan Wang
{"title":"Postprandial exercise regulates tissue-specific triglyceride uptake through angiopoietin-like proteins.","authors":"Xiaomin Liu, Yiliang Zhang, Bingqian Han, Lin Li, Ying Li, Yifan Ma, Shijia Kang, Quan Li, Lingkai Kong, Kun Huang, Bao-Liang Song, Yong Liu, Yan Wang","doi":"10.1172/jci.insight.181553","DOIUrl":"10.1172/jci.insight.181553","url":null,"abstract":"<p><p>Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2024-08-22DOI: 10.1172/jci.insight.180315
Luis R Cassinotti, Lingchao Ji, M Caroline Yuk, Aditi S Desai, Nathan D Cass, Zahara A Amir, Gabriel Corfas
{"title":"Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model.","authors":"Luis R Cassinotti, Lingchao Ji, M Caroline Yuk, Aditi S Desai, Nathan D Cass, Zahara A Amir, Gabriel Corfas","doi":"10.1172/jci.insight.180315","DOIUrl":"10.1172/jci.insight.180315","url":null,"abstract":"<p><p>Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds, a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the impact of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibit the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL, and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Also, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in CMT1A patients might help develop robust clinical tests for HHL, which are currently lacking.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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