WISP1 promotes non-alcoholic fatty liver disease and skeletal muscle insulin resistance via TLR4/JNK signaling.

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  • Additional Information
    • Source:
      Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0050222 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4652 (Electronic) Linking ISSN: 00219541 NLM ISO Abbreviation: J Cell Physiol Subsets: MEDLINE
    • Publication Information:
      Publication: New York, NY : Wiley-Liss
      Original Publication: Philadelphia, Wistar Institute of Anatomy and Biology.
    • Subject Terms:
      CCN Intercellular Signaling Proteins/*metabolism ; Insulin Resistance/*physiology ; MAP Kinase Signaling System/*physiology ; Muscle Fibers, Skeletal/*metabolism ; Non-alcoholic Fatty Liver Disease/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Signal Transduction/*physiology ; Toll-Like Receptor 4/*metabolism; 3T3-L1 Cells ; Animals ; Cell Line ; Diet, High-Fat/adverse effects ; Hepatocytes/metabolism ; Inflammation/metabolism ; Insulin/metabolism ; Lipogenesis/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/metabolism ; Phosphorylation/physiology
    • Abstract:
      Wnt1-inducible signaling pathway protein-1 (WISP1) is a Cyr61/CTGF/NOV (CCN) family matricellular protein involved in adipogenesis and low-grade inflammation in obesity. However, the roles of WISP1 in hepatic steatosis and insulin resistance in skeletal muscle remain elusive. Mouse primary hepatocytes and differentiated mouse skeletal muscle cells (C2C12) were treated with various concentrations of WISP1 and the functions and signaling pathways were analyzed by Western blot analysis. In vivo transfection for WISP1 knockdown was also performed to examine the effects of WISP1 on hepatic steatosis and skeletal muscle insulin resistance. Knockdown of WISP1 in high-fat diet-fed C57BL/6 mice significantly reduced (0.45-0.5%; p < 0.05) inflammation and JNK phosphorylation (45-50%; P < 0.01) and attenuated hepatic steatosis (approximately 55%; p < 0.001) and skeletal muscle insulin resistance (30-40%; p < 0.05). Treatment with WISP1 significantly induced inflammation (hepatocytes: approximately 500%; p < 0.01, C2C12 cells: approximately 500%; p < 0.01) and JNK phosphorylation (hepatocytes: approximately 200%; p < 0.01, C2C12 cells: approximately 280%; p < 0.01) in mouse primary hepatocytes and C2C12 mouse skeletal muscle cells. Moreover, it increased lipogenesis-associated gene expression (200-300%; p < 0.01) and accumulation of triglycerides (approximately 320%; p < 0.01) in hepatocytes, and suppressed insulin signaling (approximately 50%; p < 0.01) in C2C12 cells. These WISP1-induced effects were significantly abrogated in NFκB-, JNK-, and TLR4-knockdown hepatocytes (p < 0.05) and C2C12 cells (p < 0.05). These results indicate that WISP1 contributes to hepatic steatosis and skeletal muscle insulin resistance through a TLR4-activated inflammation/JNK signaling pathway and could be a useful therapeutic target for treatment of non-alcoholic fatty liver disease and type 2 diabetes.
      (© 2018 Wiley Periodicals, Inc.)
    • Contributed Indexing:
      Keywords: JNK; NAFLD; TLR4; WISP1; inflammation; insulin resistance
    • Accession Number:
      0 (CCN Intercellular Signaling Proteins)
      0 (CCN4 protein, mouse)
      0 (Insulin)
      0 (Proto-Oncogene Proteins)
      0 (Tlr4 protein, mouse)
      0 (Toll-Like Receptor 4)
    • Publication Date:
      Date Created: 20180111 Date Completed: 20190923 Latest Revision: 20191210
    • Publication Date:
      20231215
    • Accession Number:
      10.1002/jcp.26449
    • Accession Number:
      29319180