Abstract
A recently discovered human glycoprotein, chitinase 3-like 1 (Chi3L1), may play a role in inflammation, tissue remodeling, and visceral fat accumulation. We hypothesize that Chi3L1 gene expression is important in the development of hepatic insulin resistance characterized by the generation of pAKT, pGSK, and pERK in wild type and Chi3L1 knockout (KO) murine liver following insulin stimulation. The Chi3L1 gene and protein expression was evaluated by Real Time PCR and ELISA; lipid accumulation in hepatocytes was also assessed. To alter Chi3L1 function, three different anti-Chi3L1 monoclonal antibodies (mAbs) were administered in vivo and effects on the insulin signaling cascade and hepatic lipid deposition were determined. Transmission of the hepatic insulin signal was substantially improved following KO of the CHi3L1 gene and there was reduced lipid deposition produced by a HFD. The HFD-fed mice exhibited increased Chi3L1 expression in the liver and there was impaired insulin signal transduction. All three anti-Chi3L1 mAbs partially restored hepatic insulin sensitivity which was associated with reduced lipid accumulation in hepatocytes as well. A KO of the Chi3L1 gene reduced lipid accumulation and improved insulin signaling. Therefore, Chi3L1 gene upregulation may be an important factor in the generation of NAFLD/NASH phenotype.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in the world today and affects approximately 25% of adults in the United States
The nonalcoholic steatohepatitis (NASH) phenotype is pathologically characterized by inflammation, hepatocyte injury, lipid degeneration and fibrosis, which can advance to cirrhosis and hepatocellular carcinoma (HCC) over time [1]
Three chitinase 3-like 1 (Chi3L1) KO mice and three C57BL/6 wild type (WT) mice were fed with Chow diet (CD) and euthanized in one month to test the hypothesis that Chi3L1 may play a role in generation of hepatic insulin
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder in the world today and affects approximately 25% of adults in the United States. The Chi3L1 stimulates Th2 inflammation and M2 macrophage differentiation, inhibits oxidant injury, controls inflammasome and caspase activation, regulates TGF-β1 elaboration, contributes to antibacterial responses and activates MAP kinase (MAPK), Akt/protein kinase B and Wnt/β-catenin signaling [14,15,16]. Many of these responses are mediated by a multimeric receptor called chitosome that contains an IL-13Rα2 and a TMEM219 (TMEM) β subunit [16,17]. We provide evidence on how Chi3L1 protein expression is linked to components of the insulin cascade and alters signaling in the intact murine liver during the development of steatohepatitis [7,30] and how this effect can be partially reversed by parenteral anti-Chi3L1 mAb treatment
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