Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, 421001, China.
Department of Pathology & Immunology, Washington University in, St. Louis, MO, 63110, USA.
Int J Obes (Lond). 2018 Aug;42(8):1418-1430. doi: 10.1038/s41366-018-0151-9. Epub 2018 Jul 13.
BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation.
ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes.
ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes.
Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.
背景/目的：非酒精性脂肪性肝病（NAFLD）的特征为肝脂肪变性、胰岛素敏感性受损和慢性低度炎症。我们之前的研究表明锌-α2 糖蛋白（ZAG）可减轻肝细胞中软脂酸（PA）诱导的细胞内脂质堆积。本研究旨在进一步探讨 ZAG 在肝脂肪变性、胰岛素抵抗（IR）和炎症发展中的作用。
通过 Western blot 检测 NAFLD 患者、高脂肪饮食（HFD）诱导或遗传（ob/ob）肥胖小鼠肝脏以及 PA 处理的肝细胞中 ZAG 蛋白水平。用表达 ZAG 的腺病毒注射 C57BL/6J 小鼠，使其在 HFD 喂养一段时间以诱导肝脂肪变性、IR 和炎症，然后进行生物医学、组织学和代谢分析，以鉴定这些小鼠的病理改变。在小鼠和肝细胞中进一步探索和验证 ZAG 调节肝脂肪变性的分子机制。
ZAG 表达在 NAFLD 患者肝活检样本、肥胖小鼠肝脏和 PA 处理的肝细胞中降低。同时，ZAG 过表达通过上调脂联素和脂肪分解基因（FXR、PPARα 等）以及下调脂肪生成基因（SREBP-1c、LXR 等）来减轻细胞内脂质堆积，在肥胖小鼠以及培养的肝细胞中也是如此。ZAG 通过激活 IRS/AKT 信号转导改善胰岛素敏感性和葡萄糖耐量。此外，ZAG 显著抑制 NF-ĸB/JNK 信号通路，从而抑制肝细胞中肥胖相关的炎症反应。
我们的研究结果表明，ZAG 可通过改善肝脂肪变性、IR 和炎症来预防 NAFLD。
