Pioglitazone Reduces Hepatic Alpha-1 Antitrypsin Accumulation Through Autophagy and AMPK Activation in Alpha-1 Antitrypsin Deficient Mice.

IF 3.3 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Yuanqing Lu, Regina Oshins, Nesmine R Maptue, Qingyang Shen, Chalermchai Khemtong, Kenneth Cusi, Mark Brantly, Nazli Khodayari
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Abstract

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by accumulation of misfolded Z α-1 antitrypsin (ZAAT) in hepatocytes, leading to liver injury and metabolic dysfunction. There is no therapy to reduce ZAAT accumulation and restore proteostasis. Pioglitazone activates AMP-activated protein kinase (AMPK), enhance autophagy, and modulate ER stress responses, suggesting a potential effect on ZAAT clearance. Our objective is to examine whether pioglitazone can protect against AATD-mediated liver disease. Methods: Huh7.5 cells expressing ZAAT (HuhZ) and Pi*Z transgenic mice were used to investigate pioglitazone treatment on hepatic ZAAT accumulation, autophagy activation, and AMPK signaling. Histological, molecular, and metabolic analyses were conducted to assess changes in ZAAT content, autophagy markers, AMPK phosphorylation, and proteostasis. Results: Pioglitazone significantly reduced intracellular ZAAT and decreased lipid droplet accumulation in HuhZ cells. Pioglitazone markedly lowered hepatic ZAAT content in Pi*Z mice, suggesting enhanced degradation. This reduction was mediated through the AMPK pathway, indicated by increased phosphorylation of AMPK and ULK1. Pioglitazone induced autophagy, shown by decreased p62 and increased ATG5 and LC3B-II. This is indicative of enhanced autophagy. Although total hepatic AAT levels were reduced, PASD-positive ZAAT aggregates exhibited only a downward trend, suggesting these may be more resistant to clearance. Conclusion: These findings demonstrate pioglitazone reduces hepatic ZAAT accumulation by activating AMPK and inducing autophagy in AATD-associated liver disease, supporting its potential for therapeutic repurposing. As pioglitazone is FDA-approved with benefits for metabolic liver health, further studies are warranted to evaluate efficacy in restoring proteostasis and reducing hepatic ZAAT.

吡格列酮通过自噬和AMPK激活减少α -1抗胰蛋白酶缺陷小鼠肝脏α -1抗胰蛋白酶积累。
背景:α-1抗胰蛋白酶缺乏症(AATD)是一种以错误折叠的Z α-1抗胰蛋白酶(ZAAT)在肝细胞内积累为特征的遗传性疾病,可导致肝损伤和代谢功能障碍。目前还没有减少ZAAT积累和恢复蛋白质平衡的治疗方法。吡格列酮激活amp活化蛋白激酶(AMPK),增强自噬,调节内质网应激反应,提示对ZAAT清除有潜在影响。我们的目的是研究吡格列酮是否可以预防aatd介导的肝脏疾病。方法:采用表达ZAAT (HuhZ)的Huh7.5细胞和Pi*Z转基因小鼠,研究吡格列酮对肝脏ZAAT积累、自噬激活和AMPK信号传导的影响。通过组织学、分子和代谢分析来评估ZAAT含量、自噬标志物、AMPK磷酸化和蛋白质静止的变化。结果:吡格列酮显著降低HuhZ细胞内ZAAT,降低脂滴积聚。吡格列酮显著降低Pi*Z小鼠肝脏ZAAT含量,表明其降解能力增强。这种减少是通过AMPK途径介导的,表现为AMPK和ULK1磷酸化的增加。吡格列酮诱导自噬,表现为p62降低,ATG5和LC3B-II升高。这表明自噬增强。尽管肝脏总AAT水平降低,但pad阳性的ZAAT聚集物仅呈下降趋势,表明这些可能对清除更有抵抗力。结论:这些发现表明吡格列酮通过激活AMPK和诱导自噬来减少aatd相关肝病的肝脏ZAAT积累,支持其治疗再利用的潜力。由于吡格列酮已获得fda批准,对代谢性肝脏健康有益,因此需要进一步的研究来评估其在恢复蛋白质停滞和降低肝脏ZAAT方面的功效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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