Tirzepatide enhances liver structural integrity by promoting mitochondrial dynamics and mitophagy via PINK1/PRKN and SIRT3/NRF2 pathways in an obese-diabetic-menopausal mouse model

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-09-17 DOI:10.1016/j.tice.2025.103146

Ilitch A. Marcondes-de-Castro , Thatiany S. Marinho , Marcia B. Aguila , Carlos A. Mandarim-de-Lacerda

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引用次数: 0

Abstract

The effects on hepatic mitochondrial structure, mitophagy, and cellular homeostasis were investigated when treated with Tirzepatide (Tzp), a dual GIP/GLP-1 receptor agonist, in a mouse model combining obesity, type 2 diabetes, and menopause—conditions that collectively exacerbate metabolic dysfunction-associated steatotic liver disease (MASLD). Female C57BL/6 mice were fed either a control or high-fat, high-sucrose diet for 12 weeks, and half underwent bilateral ovariectomy to simulate menopause. Tzp was administered daily for four weeks. Liver tissue was evaluated for ultrastructural alterations, gene expression, and protein profiles. Untreated obese-diabetic and obese-diabetic-ovariectomized mice exhibited hepatocellular fat accumulation, mitochondrial swelling, and disorganized cristae, indicative of metabolic and oxidative stress. In contrast, Tzp-treated mice displayed preserved hepatic architecture and intact mitochondrial morphology. Tzp significantly downregulated autophagy genes (Ulk3, Atg5, Atg7) and key mitophagy regulators (PINK1, PRKN), reestablishing mitochondrial balance, primarily through the modulation of mitophagy and enhanced organelle stability. Simultaneously, it upregulated mitochondrial biogenesis markers (Ppargc1a, Tfam), antioxidant enzymes (SOD2, GR, GPX, CAT), and redox modulators (Sirt3, Nrf2), while normalizing oxidative stress-related genes (Nos1, Nox1). Tzp also mitigated endoplasmic reticulum (ER) stress by downregulating Atf4, Ddit3, and Gadd45 and rebalanced mitochondrial dynamics through the suppression of fission markers (Dnml1, Fis1) and the restoration of fusion mediators (Mfn1, Mfn2). Three-way ANOVA confirmed Tzp's broad regulatory effects on hepatic gene expression, while principal component analysis revealed clear transcriptional separation between treated and untreated groups. In conclusion, these findings demonstrate that Tzp preserves liver ultrastructure and restores mitochondrial dynamics, supporting its therapeutic potential in MASLD and hormone-related metabolic disorders.

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在肥胖-糖尿病-绝经小鼠模型中，替西肽通过PINK1/PRKN和SIRT3/NRF2通路促进线粒体动力学和线粒体自噬，从而增强肝脏结构完整性。

在肥胖、2型糖尿病和更年期合并的小鼠模型中，研究了tizepatide（一种双重GIP/GLP-1受体激动剂）治疗对肝脏线粒体结构、线粒体自噬和细胞稳态的影响，这些疾病共同加剧了代谢功能障碍相关的脂肪变性肝病（MASLD）。雌性C57BL/6小鼠分别饲喂对照或高脂、高糖饮食12周，其中一半进行双侧卵巢切除术以模拟更年期。每天服用Tzp，持续四周。评估肝组织的超微结构改变、基因表达和蛋白质谱。未治疗的肥胖-糖尿病和肥胖-糖尿病-去卵巢小鼠表现出肝细胞脂肪堆积、线粒体肿胀和嵴紊乱，表明代谢和氧化应激。相比之下，tzp处理的小鼠显示保存完好的肝脏结构和完整的线粒体形态。Tzp显著下调自噬基因（Ulk3, Atg5, Atg7）和关键的自噬调节因子（PINK1， PRKN），主要通过调节自噬和增强细胞器稳定性来重建线粒体平衡。同时，它上调线粒体生物发生标志物（Ppargc1a、Tfam）、抗氧化酶（SOD2、GR、GPX、CAT）和氧化还原调节剂（Sirt3、Nrf2），同时使氧化应激相关基因（Nos1、Nox1）正常化。Tzp还通过下调Atf4、Ddit3和Gadd45来减轻内质网（ER）的应激，并通过抑制裂变标记物（Dnml1、Fis1）和恢复融合介质（Mfn1、Mfn2）来重新平衡线粒体动力学。三因素方差分析证实了Tzp对肝脏基因表达的广泛调节作用，而主成分分析显示治疗组和未治疗组之间存在明显的转录分离。综上所述，这些发现表明，Tzp可以保护肝脏超微结构，恢复线粒体动力学，支持其治疗MASLD和激素相关代谢疾病的潜力。

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

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.