bims-nastce Biomed News
on NASH and T cells
Issue of 2021‒09‒12
eight papers selected by
Petra Hirsova
Mayo Clinic College of Medicine
  1. Activated natural killer cell promotes non-alcoholic steatohepatitis through mediating JAK/STAT pathway.
  2. Molecular characterization and cell type composition deconvolution of fibrosis in NAFLD.
  3. Cannabinoid receptor-1 signaling in hepatocytes and stellate cells does not contribute to NAFLD.
  4. A single-cell-type transcriptomics map of human tissues.
  5. Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases.
  6. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests.
  7. IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway.
  8. Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075.
  1. Cell Mol Gastroenterol Hepatol. 2021 Sep 07. pii: S2352-345X(21)00186-7. [Epub ahead of print]
    Activated natural killer cell promotes non-alcoholic steatohepatitis through mediating JAK/STAT pathway.
    Feixue Wang, Xiang Zhang, Weixin Liu, Yunfei Zhou, Wenchao Wei, Dabin Liu, Chi-Chun Wong, Joseph Jy Sung, Jun Yu.
      BACKGROUND & AIMS: Hepatic immune microenvironment plays a pivotal role in the development of non-alcoholic steatohepatitis (NASH). However, the role of natural killer cells (NK cells), accounting for 10-20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution.METHODS: NASH was induced in mice fed methionine- and choline-deficient diet (MCD), choline-deficient high fat diet (CD-HFD) or high fat diet (HFD) with streptozotocin injection (STAMTM model). NK cell deficient mice (Nfil3-/-) and neutralization antibody (PK136) were used in this study.
    RESULTS: Activated liver NK cells were identified with increased expression of NKG2D, CD107a, IFN-γ but decreased inhibitory NKG2A. With NK cell deficiency Nfil3-/- mice, the absence of NK cells ameliorated both MCD- and CDHF- induced NASH development with significantly decreased hepatic triglycerides, peroxides, serum ALT and AST compared to Nfil3+/+ mice. Further molecular analysis unveiled suppressed pro-inflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (IFN-γ, IL-1β, IL-12, CCL4, CCL5 and GM-CSF), which could activate hepatic JAK-STAT1/3 and NF-κB signaling and induce hepatocytes damage evidenced by elevated ROS and apoptosis rate. Moreover, neutralization antibody PK136-dependent NK cells depletion can significantly alleviate MCD induced steatohepatitis with suppressed cytokine levels and JAK-STAT1/3 activity.
    CONCLUSION: NK cells in NASH liver are activated with a more pro-inflammatory cytokine milieu, and promote NASH development via cytokine-JAK-STAT1/3 axis. Modulation of NK cells provides a potential therapeutic strategy for NASH.
    Keywords:  JAK/STAT; cytokine; natural killer cell; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.08.019
  2. Sci Rep. 2021 Sep 10. 11(1): 18045
    Molecular characterization and cell type composition deconvolution of fibrosis in NAFLD.
    Lorena Pantano, George Agyapong, Yang Shen, Zhu Zhuo, Francesc Fernandez-Albert, Werner Rust, Dagmar Knebel, Jon Hill, Carine M Boustany-Kari, Julia F Doerner, Jörg F Rippmann, Raymond T Chung, Shannan J Ho Sui, Eric Simon, Kathleen E Corey.
      Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. In adults with NAFLD, fibrosis can develop and progress to liver cirrhosis and liver failure. However, the underlying molecular mechanisms of fibrosis progression are not fully understood. Using total RNA-Seq, we investigated the molecular mechanisms of NAFLD and fibrosis. We sequenced liver tissue from 143 adults across the full spectrum of fibrosis stage including those with stage 4 fibrosis (cirrhosis). We identified gene expression clusters that strongly correlate with fibrosis stage including four genes that have been found consistently across previously published transcriptomic studies on NASH i.e. COL1A2, EFEMP2, FBLN5 and THBS2. Using cell type deconvolution, we estimated the loss of hepatocytes versus gain of hepatic stellate cells, macrophages and cholangiocytes with advancing fibrosis stage. Hepatocyte-specific functional analysis indicated increase of pro-apoptotic pathways and markers of bipotent hepatocyte/cholangiocyte precursors. Regression modelling was used to derive predictors of fibrosis stage. This study elucidated molecular and cell composition changes associated with increasing fibrosis stage in NAFLD and defined informative gene signatures for the disease.
    DOI:  https://doi.org/10.1038/s41598-021-96966-5
  3. J Clin Invest. 2021 Sep 09. pii: 152242. [Epub ahead of print]
    Cannabinoid receptor-1 signaling in hepatocytes and stellate cells does not contribute to NAFLD.
    Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K Bence, Mingjian Lu, Carlos M Castorena, Shangang Zhao, Joel K Elmquist, Philipp E Scherer, Jay D Horton.
      The endocannabinoid system regulates appetite and energy expenditure and inhibitors of the cannabinoid receptor-1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 receptors in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 receptors in hepatocytes did not alter the development of NAFLD in mice fed a high sucrose high fat diet or high fat diet (HFD). Similarly, deletion of CB-1 deletion specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD nor did it protect mice for carbon tetrachloride (CCl4)-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.
    Keywords:  Drug therapy; Fibrosis; Hepatology; Metabolism; Mouse models
    DOI:  https://doi.org/10.1172/JCI152242
  4. Nat Genet. 2021 Sep;53(9): 1275
    A single-cell-type transcriptomics map of human tissues.
    Ornob Alam.
      
    DOI:  https://doi.org/10.1038/s41588-021-00938-4
  5. Int J Mol Sci. 2021 Aug 24. pii: 9139. [Epub ahead of print]22(17):
    Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases.
    Chang-Kee Hyun.
      Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
    Keywords:  Crohn’s disease; gut dysbiosis; gut microbiota-derived metabolites; inflammatory bowel disease; intestinal immune function; intestinal permeability; non-alcoholic fatty liver disease; obesity; type 2 diabetes; ulcerative colitis
    DOI:  https://doi.org/10.3390/ijms22179139
  6. Nat Rev Gastroenterol Hepatol. 2021 Sep 10.
    Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests.
    Mojgan Masoodi, Amalia Gastaldelli, Tuulia Hyötyläinen, Enara Arretxe, Cristina Alonso, Melania Gaggini, Julia Brosnan, Quentin M Anstee, Oscar Millet, Pablo Ortiz, Jose M Mato, Jean-Francois Dufour, Matej Orešič.
      Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
    DOI:  https://doi.org/10.1038/s41575-021-00502-9
  7. Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2103444118. [Epub ahead of print]118(37):
    IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway.
    Felipe Valença-Pereira, Qian Fang, Isabelle J Marié, Emily L Giddings, Karen A Fortner, Rui Yang, Alejandro V Villarino, Yina H Huang, David A Frank, Haitao Wen, David E Levy, Mercedes Rincon.
      Interleukin 6 (IL-6) is known to regulate the CD4 T cell function by inducing gene expression of a number of cytokines through activation of Stat3 transcription factor. Here, we reveal that IL-6 strengthens the mechanics of CD4 T cells. The presence of IL-6 during activation of mouse and human CD4 T cells enhances their motility (random walk and exploratory spread), resulting in an increase in travel distance and higher velocity. This is an intrinsic effect of IL-6 on CD4 T-cell fitness that involves an increase in mitochondrial Ca2+ Although Stat3 transcriptional activity is dispensable for this process, IL-6 uses mitochondrial Stat3 to enhance mitochondrial Ca2+-mediated motility of CD4 T cells. Thus, through a noncanonical pathway, IL-6 can improve competitive fitness of CD4 T cells by facilitating cell motility. These results could lead to alternative therapeutic strategies for inflammatory diseases in which IL-6 plays a pathogenic role.
    Keywords:  CD4 T cells; STAT3; interleukin-6; mitochondrial calcium; motility
    DOI:  https://doi.org/10.1073/pnas.2103444118
  8. Nat Metab. 2021 Sep 06.
    Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075.
    Yudong Ji, Zhenlong Luo, Hong Gao, Felipe Castellani Gomes Dos Reis, Gautam Bandyopadhyay, Zhongmou Jin, Kameswari Ananthakrishnan Manda, Roi Isaac, Meixiang Yang, Wenxian Fu, Wei Ying, Jerrold M Olefsky.
      In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4 weeks high-fat diet), hepatocytes secrete exosomes that enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal microRNA miR-3075, which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and small interfering RNA depletion of FA2H in adipocytes, myocytes and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16-18 weeks of a high-fat diet), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signalling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes that express high levels of the insulin-sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.
    DOI:  https://doi.org/10.1038/s42255-021-00444-1
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