Despite increasing evidences has highlighted the importance of mitochondria-lipid droplet (LD) coupling in maintaining lipid homeostasis, little progress in unraveling the role of mitochondria-LD coupling in hepatic lipid metabolism has been made. Additionally, diallyl disulfide (DADS), a garlic organosulfur compound, has been proposed to prevent hepatic steatosis; however, no studies have focused on the molecular mechanism to date. To address these gaps, this study investigated the systemic control mechanisms of mitochondria-LD coupling regulating hepatic lipid metabolism, and also explored their function in the process of DADS alleviating hepatic steatosis. To this end, an animal model of lipid metabolism, yellow catfish Pelteobagrus fulvidraco were fed four different diets (control, high-fat, DADS and high-fat + DADS diet) in vivo for 8 weeks; in vitro experiments were conducted to inhibit Mfn2/Atgl-mediated mitochondria-LD coupling in isolated hepatocytes. The key findings are: (1) the activations of hepatic LDs lipolysis and mitochondrial β-oxidation are likely the major drivers for DADS alleviating hepatic steatosis; (2) the underlying mechanism is that DADS enhances mitochondria-LD coupling by promoting the interaction between mitochondrion-localized Mfn2 with LD-localized Atgl, which facilitates the hepatic LDs lipolysis and the transfer of fatty acids (FAs) from LDs to mitochondria for subsequent β-oxidation; (3) Mfn2-mediated mitochondrial fusion facilitates mitochondria to form more PDM, which possess higher β-oxidation capacity in hepatocytes. Significantly, the present research unveils a previously undisclosed mechanism by which Mfn2/Atgl-mitochondria-LD coupling relieves hepatic LDs accumulation, which is a conserved strategy from fish to tetrapod. This study provides another dimension for mitochondria-LD coupling and opens up new avenues for the therapeutic interventions in hepatic steatosis.

中文翻译：

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二烯丙基二硫化物通过从鱼到四足动物的保守机制缓解肝脂肪变性：增强 Mfn2/Atgl 介导的脂滴-线粒体偶联


尽管越来越多的证据强调了线粒体-脂滴 （LD） 偶联在维持脂质稳态中的重要性，但在揭示线粒体-LD 偶联在肝脏脂质代谢中的作用方面几乎没有取得进展。此外，二烯丙基二硫化物 （DADS） 是一种大蒜有机硫化合物，已被提议用于预防肝脂肪变性;然而，迄今为止还没有研究关注其分子机制。为了解决这些差距，本研究探讨了线粒体-LD 偶联调节肝脏脂质代谢的全身控制机制，并探讨了它们在 DADS 缓解肝脂肪变性过程中的功能。为此，脂质代谢动物模型黄鲶鱼 Pelteobagrus fulvidraco 在体内饲喂四种不同的饮食（对照、高脂肪、DADS 和高脂肪 + DADS 饮食），持续 8 周;进行体外实验以抑制离体肝细胞中 Mfn2/Atgl 介导的线粒体-LD 偶联。主要发现是： （1） 肝脏 LDs 脂肪分解和线粒体 β 氧化的激活可能是 DADS 缓解肝脂肪变性的主要驱动力;（2） 潜在机制是 DADS 通过促进线粒体定位的 Mfn2 与 LD 定位的 Atgl 之间的相互作用来增强线粒体-LD 偶联，从而促进肝脏 LDs 脂肪分解和脂肪酸 （FAs） 从 LDs 转移到线粒体以进行随后的β氧化;（3） Mfn2 介导的线粒体融合促进线粒体形成更多的 PDM，PDM 在肝细胞中具有更高的 β-氧化能力。值得注意的是，本研究揭示了一种以前未公开的机制，即 Mfn2/Atgl-线粒体-LD 偶联缓解肝脏 LDs 积累，这是一种从鱼类到四足动物的保守策略。 本研究为线粒体-LD 偶联提供了另一个维度，并为肝脂肪变性的治疗干预开辟了新的途径。