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.

中文翻译：

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几丁质酶3样1蛋白在非酒精性脂肪肝肝胰岛素抵抗发病机制中的作用

最近发现的人类糖蛋白，几丁质酶 3 样 1 (Chi3L1)，可能在炎症、组织重塑和内脏脂肪堆积中发挥作用。我们假设 Chi3L1 基因表达在肝脏胰岛素抵抗的发展中很重要，其特征是在胰岛素刺激后野生型和 Chi3L1 敲除 (KO) 小鼠肝脏中产生 pAKT、pGSK 和 pERK。通过实时PCR和ELISA评估Chi3L1基因和蛋白的表达；还评估了肝细胞中的脂质积累。为了改变 Chi3L1 功能，在体内施用了三种不同的抗 Chi3L1 单克隆抗体 (mAb)，并确定了对胰岛素信号级联和肝脏脂质沉积的影响。在 KO CHi3L1 基因后，肝脏胰岛素信号的传递得到显着改善，并且由 HFD 产生的脂质沉积减少。HFD 喂养的小鼠在肝脏中表现出增加的 Chi3L1 表达，并且胰岛素信号转导受损。所有三种抗 Chi3L1 mAb 都部分恢复了肝脏胰岛素敏感性，这也与肝细胞中脂质积累减少有关。Chi3L1 基因的 KO 减少了脂质积累并改善了胰岛素信号传导。因此，Chi3L1基因上调可能是NAFLD/NASH表型产生的重要因素。所有三种抗 Chi3L1 mAb 都部分恢复了肝脏胰岛素敏感性，这也与肝细胞中脂质积累减少有关。Chi3L1 基因的 KO 减少了脂质积累并改善了胰岛素信号传导。因此，Chi3L1基因上调可能是NAFLD/NASH表型产生的重要因素。所有三种抗 Chi3L1 mAb 都部分恢复了肝脏胰岛素敏感性，这也与肝细胞中脂质积累减少有关。Chi3L1 基因的 KO 减少了脂质积累并改善了胰岛素信号传导。因此，Chi3L1基因上调可能是NAFLD/NASH表型产生的重要因素。