bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2022–10–02
two papers selected by
Matías Eduardo González Quiroz, Worker’s Hospital
  1. Hepatic Deletion of X-box Binding Protein 1 in Farnesoid X Receptor Null Mice Leads to Enhanced Liver Injury.
  2. The unfolded protein response gene Ire1α is required for tissue renewal and normal differentiation in the mouse tongue and esophagus.
  1. J Lipid Res. 2022 Sep 23. pii: S0022-2275(22)00122-5. [Epub ahead of print] 100289
    Hepatic Deletion of X-box Binding Protein 1 in Farnesoid X Receptor Null Mice Leads to Enhanced Liver Injury.
    Xiaoying Liu, Mahmoud Khalafalla, Chuhan Chung, Yevgeniy Gindin, Susan Hubchak, Brian LeCuyer, Alyssa Kriegermeier, Danny Zhang, Wei Qiu, Xianzhong Ding, Deyu Fang, Richard Green.
      Farnesoid X receptor (FXR) regulates bile acid metabolism, and FXR null (Fxr-/-) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway is a protective unfolded protein response (UPR) pathway activated in response to ER stress. Here, we sought to determine the role of the IRE1α/XBP1 pathway in hepatic bile acid toxicity using the Fxr-/- mouse model. Western blotting and qPCR analysis demonstrated that hepatic XBP1 and other UPR pathways were activated in 24-week-old Fxr-/- compared to 10-week-old Fxr-/- mice, but not in WT mice. To further determine the role of the liver XBP1 activation in older Fxr-/- mice, we generated mice with whole-body FXR and liver-specific XBP1 double knockout (DKO, Fxr-/-Xbp1LKO) and Fxr-/-Xbp1fl/fl single knockout (SKO) mice and characterized the role of hepatic XBP1 in cholestatic liver injury. Histologic staining demonstrated increased liver injury and fibrosis in DKO compared to SKO mice. RNA-seq revealed increased gene expression in apoptosis, inflammation, and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein (CHOP) pathway and cell cycle marker Cyclin D1 were also activated in DKO mice. Furthermore, we found total hepatic bile acid levels were similar between the two genotypes. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors. In conclusion, the hepatic XBP1 pathway is activated in older Fxr-/- mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses.
    Keywords:  Apoptosis; Bile acids; Bile salts; Cell signaling; Cholestatic liver injury; Inflammation; Inositol-requiring enzyme 1α; Liver tumor; Nuclear receptor; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.jlr.2022.100289
  2. Dev Biol. 2022 Sep 27. pii: S0012-1606(22)00180-4. [Epub ahead of print]
    The unfolded protein response gene Ire1α is required for tissue renewal and normal differentiation in the mouse tongue and esophagus.
    Fiona E Chalmers, Saie Mogre, Bipin Rimal, Jeongin Son, Andrew D Patterson, Douglas B Stairs, Adam B Glick.
      The IRE1α-XBP1s signaling branch of the unfolded protein response is a well-characterized survival pathway that allows cells to adapt to and resolve endoplasmic reticulum stress. Recent data has broadened our understanding of IRE1α-XBP1s signaling beyond a stress response and revealed a physiological mechanism required for the differentiation and maturation of a wide variety of cell types. Here we provide evidence that the IRE1α-XBP1s signaling pathway is required for the proliferation and maturation of basal keratinocytes in the mouse tongue and esophageal epithelium. Mice with conditional targeted deletion of either Ire1α or Xbp1 in keratin 14 expressing basal keratinocytes displayed severe thinning of the lingual and esophageal mucosa that rendered them unable to eat. In IRE1α null epithelium harvested at an earlier timepoint, genes regulating cell proliferation, cell-cell adhesion, and keratinization were significantly downregulated; indirect immunofluorescence revealed fewer proliferating basal keratinocytes, downregulation of E-cadherin, and thinning of the loricrin-positive granular and cornified layers. The number of Tp63-positive basal keratinocytes was reduced in the absence of IRE1α, and expression of the Wnt pathway transcription factor LEF1, which is required for the proliferation of lingual transit amplifying cells, was also significantly downregulated at the transcript and protein level. Together these results reveal an essential role for IRE1α-XBP1s in the maintenance of the stratified squamous epithelial tissue of the tongue and esophagus.
    Keywords:  Differentiation; Endoplasmic reticulum stress; Keratinocytes; Stratified squamous epithelium; Unfolded protein response; Wnt pathway
    DOI:  https://doi.org/10.1016/j.ydbio.2022.09.009
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