BACKGROUND & AIMS Heat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals. METHODS Double transgenic mice overexpressing Hsp72 (gene Hspa1a) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with either a methionine choline-deficient (MCD; 8 weeks) or a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were treated with palmitic acid. RESULTS Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation. CONCLUSIONS Our results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions. LAY SUMMARY HSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.

中文翻译：

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Hsp72 通过减轻肝细胞死亡、氧化应激和 JNK 信号传导来保护肝损伤

背景与目的 热休克蛋白 (Hsp) 72 是一种分子伴侣，具有广泛的细胞保护功能，并在应激反应中上调。为了确定其肝功能，我们研究了它在人类肝脏疾病中的表达及其在新产生的转基因动物中的生物学意义。方法 在组织特异性四环素诱导系统（Hsp​​72-LAP 小鼠）的控制下，制备过表达 Hsp72（基因 Hspa1a）的双转基因小鼠。单次注射对乙酰氨基酚 (APAP) 可诱发急性肝损伤。饲喂蛋氨酸胆碱缺乏（MCD；8 周）或补充 3,5-二乙氧基羰基-1,4-二氢可利丁的饮食（DDC；12 周）用于诱导脂毒性损伤和 Mallory-Denk 体 (MDB)分别形成。用棕榈酸处理原代肝细胞。结果 非酒精性脂肪性肝炎和慢性丙型肝炎感染患者的 HSP72 水平升高。这些水平随着肝脏炎症的程度而增加，并且在用白细胞介素 (IL)-1β 或 IL-6 治疗后诱导 HSP72 表达。Hsp72-LAP 小鼠表现出强大的肝细胞特异性 Hsp72 过表达。来自这些动物的原代肝细胞对隔离诱导的压力具有更强的抵抗力，并且 Hsp72-LAP 小鼠在体内表现出较低水平的肝损伤。过表达 Hsp72 的小鼠具有较少的 APAP 蛋白加合物，并且受到保护免受氧化应激和 APAP-/MCD 诱导的细胞死亡。Hsp72-LAP 小鼠和/或肝细胞显示出显着减弱的 Jnk 激活。Hsp72 的过表达不影响脂肪变性或 MDB 形成的程度。结论 我们的结果表明 HSP72 诱导发生在人类肝病中，因此，HSP72 因其广泛的保肝功能而成为一个有吸引力的治疗靶点。总结 HSP72 构成一种应激诱导的保护性蛋白质。我们的数据表明它在慢性丙型肝炎和非酒精性脂肪性肝炎患者中上调。此外，过表达 Hsp72 的小鼠免受各种形式的肝脏压力。