Donepezil alleviates hepatic steatosis by mitigating ER stress via the AMPK/autophagy pathway

IF 3.8 3区 医学 Q2 CELL BIOLOGY
Wonjun Cho , Sung Woo Choi , Do Su Lim , Hyeon Ji Gwon , A.M. Abd El-Aty , Hacı Ahmet Aydemir , Soon Auck Hong , Ji Hoon Jeong , Tae Woo Jung
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Abstract

Donepezil (Do), a drug known for its ability to reduce neuronal inflammation and for its use in the treatment of Alzheimer's disease, has shown promise in combating hepatic lipid accumulation in hyperlipidemic conditions and endoplasmic reticulum (ER) stress, a factor associated with alterations in hepatic lipid metabolism. However, the mechanisms by which these problems are alleviated have not been fully elucidated. In this study, we investigated the effects of Do on hepatic lipid metabolism through both in vitro and in vivo studies. We examined the expression of proteins associated with lipogenesis and ER stress via immunoblot analysis, and hepatic lipid accumulation was assessed via oil red O staining. In addition, autophagosome formation was analyzed by counting MDC-positive cells. Our results demonstrated that Do treatment improved hepatic lipid metabolism and reduced the expression of ER stress markers, resulting in decreased lipogenic lipid deposition and apoptosis in the hepatocytes and livers of hyperlipidemic mice. Mechanistically, knocking down AMPK or inhibiting autophagy with 3-methyladenine (3 MA) attenuated the effects of Do on palmitate-exposed hepatocytes. These results suggest that Do alleviates hepatic ER stress via the AMPK/autophagy pathway and AMPK-mediated fatty acid oxidation, resulting in improved hepatic lipid metabolism and reduced hepatic steatosis and apoptosis. Our study provides evidence that Do may be a promising therapeutic approach for Alzheimer's disease patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Abstract Image

多奈哌齐通过AMPK/自噬途径减轻内质网应激,从而减轻肝脂肪变性。
多奈哌齐(Do)是一种以减少神经元炎症和治疗阿尔茨海默病的能力而闻名的药物,在对抗高脂血症和内质网(ER)应激(与肝脏脂质代谢改变相关的因素)的肝脏脂质积累方面显示出了希望。然而,缓解这些问题的机制尚未得到充分阐明。在本研究中,我们通过体外和体内实验研究了Do对肝脏脂质代谢的影响。我们通过免疫印迹分析检测了与脂肪生成和内质网应激相关的蛋白质的表达,并通过油红O染色评估了肝脏脂质积累。此外,通过计数mdc阳性细胞来分析自噬体的形成。我们的研究结果表明,Do治疗改善了肝脏脂质代谢,降低了内质网应激标志物的表达,导致高脂血症小鼠肝细胞和肝脏的脂质沉积和凋亡减少。机制上,敲除AMPK或用3-甲基腺嘌呤(3MA)抑制自噬可减弱Do对棕榈酸暴露的肝细胞的影响。这些结果表明,Do通过AMPK/自噬途径和AMPK介导的脂肪酸氧化来缓解肝脏内质网应激,从而改善肝脏脂质代谢,减少肝脏脂肪变性和细胞凋亡。我们的研究提供了证据,表明Do可能是阿尔茨海默病合并代谢功能障碍相关脂肪变性肝病(MASLD)患者的一种有希望的治疗方法。
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来源期刊
Molecular and Cellular Endocrinology
Molecular and Cellular Endocrinology 医学-内分泌学与代谢
CiteScore
9.00
自引率
2.40%
发文量
174
审稿时长
42 days
期刊介绍: Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.
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