美国爱荷华大学卡佛医学院Yang Ling小组取得一项新突破。他们发现了肥胖破坏垂体-肝未折叠蛋白质应激反应交流，导致非酒精性脂肪肝病发展。这一研究成果于2024年5月7日发表在国际顶尖学术期刊《细胞—代谢》上。

研究人员表示，肥胖改变控制肝脏免疫代谢稳态的垂体激素水平，其失调导致非酒精性脂肪性肝病(NAFLD)。然而，肥胖对垂体内稳态的影响在很大程度上是未知的。

研究团队在肥胖小鼠和人类的脑垂体中发现了钝化的未折叠蛋白反应(UPR)，但炎症特征升高。此外，该团队发现肥胖会导致垂体炎症，导致垂体肌醇需求酶1α (IRE1α)-X-框结合蛋白1 (XBP1) UPR分支受损，该分支对于防止垂体内分泌缺陷和非酒精性脂肪性肝病(NAFLD)进展至关重要。

有趣的是，垂体IRE1缺失导致甲状腺功能减退，并抑制甲状腺激素受体B (THRB)介导的Xbp1在肝脏中的激活。相反，激活肝脏THRB-XBP1轴可改善垂体UPR缺陷小鼠的非酒精性脂肪性肝病。他们的研究提供了肥胖诱导的垂体内细胞缺陷的第一个证据和机制，以及垂体-肝脏UPR交流在非酒精性脂肪性肝病进展中的病理生理作用。

附：英文原文

Title: Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression

Author: Qingwen Qian, Mark Li, Zeyuan Zhang, Shannon W. Davis, Kamal Rahmouni, Andrew W. Norris, Huojun Cao, Wen-Xing Ding, Gkhan S. Hotamisligil, Ling Yang

Issue&Volume: 2024-05-07

Abstract: Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis,dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However,the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, weuncovered a blunted unfolded protein response (UPR) but elevated inflammatory signaturesin pituitary glands of obese mice and humans. Furthermore, we found that obesity inflamesthe pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-bindingprotein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrinedefects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidismand suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLDin mice with pituitary UPR defect. Our study provides the first evidence and mechanismof obesity-induced intra-pituitary cellular defects and the pathophysiological roleof pituitary-liver UPR communication in NAFLD progression.

DOI: 10.1016/j.cmet.2024.04.014

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00134-7