轻度线粒体解偶联用于真正的异位脂质处理。
Mild Mitochondrial Uncoupling for True Ectopic Lipid Disposal.
作者信息
Lee Hui-Young
机构信息
Laboratory of Mitochondria and Metabolic Diseases, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea.
出版信息
Int J Mol Sci. 2025 Aug 11;26(16):7740. doi: 10.3390/ijms26167740.
Ectopic lipid accumulation is a core contributor to insulin resistance and metabolic diseases, including type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Conventional therapies have primarily focused on redistributing lipid burden across tissues or modulating specific pathways. However, this often causes compensatory responses that merely shift the burden rather than resolve the underlying lipid excess. In this review, we introduce the concept of the ballooning effect, wherein single-target interventions inadvertently exacerbate lipid accumulation in non-target tissues. We then explore fundamental strategies for true lipid disposal, which aim either to prevent lipid influx or to promote complete lipid oxidation. Among these, mild mitochondrial uncoupling emerges as a promising solution. By dissipating substrate energy as heat, mitochondrial uncoupling reduces ectopic lipid burden without relying on redistribution. Recent advances have yielded safer chemical uncouplers and novel endogenous protein-based mechanisms that enable controlled uncoupling with minimal toxicity. Together, these provide a new framework for next-generation metabolic therapies that move beyond lipid redistribution and aim for a true lipid disposal, potentially offering a safe and effective strategy.
异位脂质积累是胰岛素抵抗和代谢性疾病的核心促成因素,这些疾病包括2型糖尿病、血脂异常和非酒精性脂肪性肝病。传统疗法主要集中于在不同组织间重新分配脂质负担或调节特定途径。然而,这通常会引发代偿反应,只是转移了负担,而不是解决潜在的脂质过剩问题。在本综述中,我们引入了“气球效应”的概念,即单一靶点干预会无意中加剧非靶组织中的脂质积累。然后,我们探索真正的脂质清除的基本策略,其目的要么是防止脂质流入,要么是促进脂质完全氧化。其中,轻度线粒体解偶联是一个有前景的解决方案。通过将底物能量以热量形式耗散,线粒体解偶联减少了异位脂质负担,而不依赖于重新分配。最近的进展产生了更安全的化学解偶联剂和新的基于内源性蛋白质的机制,能够以最小的毒性实现可控解偶联。这些共同为新一代代谢疗法提供了一个新框架,该疗法超越了脂质重新分配,旨在实现真正的脂质清除,可能提供一种安全有效的策略。