LSDP5在肝脏脂毒性损伤中的作用及机制

Metabolic disorders of non-esterified fatty acids (NEFA) are the main causes of lipotoxic liver injury. In mammalian cells, NEFA is stored in lipid droplets (LD) in the form of triglyceride (TG), and therefore the metabolic disorders of LD could lead to the lipotoxic injury in the liver. As a lipid droplet-associated protein, LSDP5 mainly expressed in oxidative tissues, such as liver and heart, has been considered as an important molecule in lipid metabolism by our group and others, but its explicit roles and mechanism in lipid metabolism remain to be clarified. Our previous results indicated that the hepatocytes with overexpressed LSDP5 are resistant to lipotoxic liver injury induced by NEFA. Meanwhile,the lipotoxic injury was developed in the liver of LSDP5 knockout mouse, while the content of TG was decreased. Here, we believed that LSDP5 could protect the LD against the lipolysis, and inhibit the development of lipotoxic liver injury induced by the metabolism of excessive NEFA. In order to clarify the explicit roles and mechanisms of LSDP5 in hepatic lipotoxicity, we generated knockout mouse to determine the roles of LSDP5 in hepatic lipid metabolism and lipotoxic liver injury induced by NEFA, and reveal physiological and molecular mechanisms of lipotoxic injury in the liver of LSDP5 knockout mouse, and elucidate the molecular mechanisms of LSDP5 in regulating the metabolism of lipid droplet, and then to discuss the relationship between the expression of LSDP5 and NASH. Our study could contribute not only to a better understanding about the relationship between the metabolism of lipid droplet and lipotoxic liver injury, but also the prevention and therapy of hepatic diseases, such as steatosis and NASH.

非酯化脂肪酸（NEFA）代谢异常是诱发肝脏脂毒性损伤的主要原因，而细胞内NEFA主要以甘油三酯（TG）的形式储存在脂滴（LD）中，因此脂滴代谢异常与肝脏脂毒性损伤的发生有着密切关系。脂滴表面蛋白LSDP5主要表达于肝脏和心脏等脂肪代谢活跃组织，但其功能尚未明确。我们发现过表达LSDP5的肝细胞能够抵抗NEFA诱导的凋亡，而LSDP5敲除小鼠肝脏TG含量降低的同时却出现肝脏损伤，我们推测LSDP5主要功能是阻止脂滴水解，抑制过量NEFA代谢诱发的脂毒性损伤。为了深入研究，本研究拟利用LSDP5敲除小鼠和原代肝细胞，确定LSDP5在肝脏脂肪和脂滴代谢中的作用，揭示LDSP5缺失诱发肝细胞脂毒性损伤的生理学过程和分子机制，阐明LSDP5调控脂滴代谢的分子机制，探讨LSDP5与非酒精性脂肪性肝炎（NASH）之间的关系。本研究结果不仅有助于认识脂滴的代谢过程，同时对NASH等疾病的诊治也具有重要意义

非酒精性脂肪性肝病（NAFLD）是代谢综合征等疾病在肝脏的重要表现形式，其主要病理特征是弥漫性肝细胞脂肪变性。目前研究认为，尽管脂质过度沉积与NAFLD的发生发展密切相关，但肝细胞内的中性脂质并不是诱发非酒精性脂肪性肝炎的直接原因，非酒精性脂肪性肝炎发生的核心是肝细胞内过量的游离脂肪酸代谢所导致的脂毒性。过量的FFA在肝细胞中主要以甘油三酯的形式储存在脂滴中。因此，脂滴代谢异常与肝脏脂毒性损伤密切相关。脂滴以前被认为仅仅是一个细胞内储存中性脂质的结构，但目前大量研究认为，脂滴也是一个代谢活跃的多功能细胞器，在细胞的脂质储积、能量供应、膜结构形成、病毒复制和蛋白降解等过程中发挥着重要作用。脂滴主要由三部分组成，包括中性脂质的核心，覆盖于其表面的单层磷脂以及镶嵌在磷脂层上的脂滴蛋白。其中，Perilipin家族是一组重要的脂滴蛋白，在调控脂滴代谢和维持细胞内脂质平衡中发挥着重要的作用。经研究发现，Plin5的表达水平与NAFLD的发生发展密切相关，Plin5能够与ATGL的共激活因子CGI-58相互作用，抑制ATGL的活性，减少肝细胞内脂滴的脂解。Plin5缺失的肝细胞中，脂滴表面CGI-58与ATGL结合增加，ATGL脂解活性被激活，导致肝细胞中脂滴含量减少，FFA含量增加。肝细胞中升高的FFA激活PPARα，导致其下游一系列与脂肪代谢密切相关的分子的表达。同时线粒体增殖，氧化磷酸化能力增强，增加β氧化以清除细胞内过多的FFA。肝细胞内过多的FFA氧化导致ROS生成增加，进而出现脂质过氧化、氧化应激、内质网应激以及炎症反应，最终导致肝脏脂毒性损伤。在脂滴形成方面，Plin5和Cideb缺失能够相互促进彼此的表达，并且Plin5能够与Cideb相互作用。Plin5能够增加肝细胞中脂滴的数量，而Cideb能够促进脂滴的融合，二者共同参与肝细胞脂滴的形成过程。但是Plin5和Cideb的相互作用在肝脏脂滴形成过程中的具体作用仍有待深入研究。

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