脂滴膜转运蛋白Rab18与脂质代谢的关系研究

脂滴是动物细胞内储存脂质的一种亚细胞器。脂滴表面存在多种脂滴周围相关蛋白,参与脂质动态平衡的调节,防止脂质代谢异常的发生。其中,Rab18作为脂滴周围相关蛋白中的一种,在脂质代谢的调节、信号的转导、膜运输等多种生理功能中发挥重要作用。对于Rab18与脂质代谢之间关系的研究,为动脉粥样硬化、糖尿病、非酒精性脂肪肝及肥胖等多种代谢性疾病的防治发挥重要作用,本文就Rab18与细胞脂质代谢之间的关系研究作一综述。     

Adipophilin在不同组织和器官中的功能

Adipophilin（ADFP）是一种脂滴周围主要的相关蛋白,它大量分布在脂质蓄积正常或不正常的细胞中,是脂质蓄积的一个特异性标记物。它在脂肪细胞分化早期就有很高的表达,但当脂肪细胞成熟后,它的表达就明显减少。ADFP在很多组织器官中都发挥重要作用,它不仅参与脂肪细胞的脂质代谢、脂滴的形成及肝内三酰甘油（TO）的合成与代谢,还能促进巨噬细胞、平滑肌细胞的泡沫化,长链脂肪酸的摄取,乳汁的分泌等。ADFP的表达异常与动脉粥样硬化、胰岛素抵抗和肿瘤等病理过程密切相关。     

脂滴包被蛋白2在动脉粥样硬化中的作用

动脉粥样硬化性心血管疾病严重威胁着人类生命健康,其中脂质代谢异常和炎症反应是其重要的发病机制。脂滴是细胞内储存脂质的一种亚细胞器,其表面存在多种脂滴包被蛋白,参与调控脂质动态平衡。脂滴包被蛋白2(Plin2)作为脂滴包被蛋白的一种,在脂质代谢的调节、脂肪酸的氧化及炎症反应等多种生理功能中发挥重要作用。近年来,越来越多的研究发现Plin2在动脉粥样硬化的发生发展中扮演着重要的角色。因此,本文主要综述Plin2在胆固醇代谢、脂质合成、自噬和炎症反应等过程中发挥的作用,进一步阐述其与动脉粥样硬化之间的关系。     

脂酰辅酶A长链合成酶3及其相关疾病

脂滴(lipid droplets)是细胞内脂质贮存和调节细胞脂质稳态的重要细胞器,其表面具有多种脂滴相关蛋白质。长链酰基辅酶A合成酶家族的成员脂酰辅酶A长链合成酶3(acyl CoA long chain synthetase 3,ACSL3)即脂滴相关蛋白质的一种,也是生物合成过程中必需的酶之一。ACSL3广泛分布于大多数细胞中的脂滴表面,其在脂滴的合成、自噬的调节和细胞铁死亡等多种病理生理过程中发挥着不同的作用。此外,多项研究表明,ACSL3还广泛参与到多种疾病的发生发展,包括动脉粥样硬化、非酒精性脂肪肝病、糖尿病和肿瘤等。当前,国内对ACSL3的研究相对集中于ACSL3与动物育种和生长的关系,而对ACSL3在脂质代谢中的作用机制及其与疾病的关系鲜有报道。本文基于国内外对ACSL3的研究,对该基因的结构、在细胞脂代谢中的作用机制及其相关疾病进行归纳,进一步探究ACSL3在脂滴的合成、自噬、铁死亡过程中的作用,为防治动脉粥样硬化、非酒精性脂肪肝病、糖尿病(glucose)等多种ACSL3相关疾病提供新的理论依据。     

脂肪甘油三酯水解酶的研究进展

胰岛素抵抗等代谢疾病的发生与脂代谢紊乱密切相关。细胞中的脂肪主要储存在一个以中性脂为核的细胞器——脂滴(lipid droplet,LD)中。脂肪甘油三酯水解酶(adiposetriglyceride lipase,ATGL)是在脂滴上发现的水解甘油三酯的脂肪酶。除脂肪组织外,ATGL也广泛存在于骨骼肌等多种非脂肪组织中,并发挥着重要的生理功能。越来越多的研究表明,ATGL与中性脂质贮存异常、胰岛素抵抗等代谢疾病密切相关。运动可以通过改变ATGL的表达起到调控脂代谢的作用,进而在防治胰岛素抵抗等代谢疾病中发挥作用。     

敲除Adipophilin基因对脂质代谢相关疾病的作用

Adipophilin是PAT (perilipin/adipophilin/Tip47)蛋白家族的一个成员,定位于细胞质和细胞内的脂滴表面.Adipophilin能促进脂质蓄积和细胞内脂滴的形成,在泡沫细胞的形成中起重要作用,是动脉粥样硬化脂质蓄积的一个标记物.Adipophilin基因敲除小鼠能预防高脂饮食诱导的脂肪肝产生,且在脂肪组织分化过程中也起着一定的作用.本文概述了adipophilin在细胞内脂质代谢中的作用.     

脂肪分化相关蛋白的研究进展

细胞内脂滴是一种代谢活跃的细胞器,脂滴表面蛋白在脂滴的代谢调节中起到了重要作用。ADRP是一种重要的脂滴表面蛋白,在机体组织和细胞内广泛表达。脂肪肝、动脉粥样硬化、糖尿病等均伴随脂质的异常蓄积,近年来的研究表明ADRP参与这些疾病的发生发展。本文就ADRP在各组织和器官正常的生理功能以及对疾病状态的调控加以综述。     

骨骼肌细胞中UBXD8的敲除及其对脂质代谢的影响

UBXD8是能与p97/VCP相互作用共同参与内质网相关的泛素化后蛋白质降解过程的膜蛋白.新近的脂滴蛋白质组学研究表明UBXD8能够定位到脂滴上,同时有研究表明UBXD8调控甘油三酯的代谢.但是UBXD8调控甘油三酯代谢的分子机制并不清楚.因此我们采用改良的CRISPR/Cas9技术敲除小鼠成骨骼肌细胞C2C12中的UBXD8.从筛选出来的26个可能的UBXD8敲除单克隆细胞系中鉴定获得了2个确切的UBXD8敲除单克隆细胞系.研究表明,敲除UBXD8没有显著改变脂滴上蛋白质的分布,但敲除UBXD8增加了细胞内中性脂的累积.同时敲除UBXD8可缓解棕榈酸引起的胰岛素抵抗和抵抗棕榈酸引起的细胞凋亡.当在敲除UBXD8的细胞中重新过表达UBXD8后,细胞再次出现了棕榈酸引起的胰岛素抵抗及细胞凋亡.这些数据表明UBXD8在细胞脂质代谢及其异常所引起的胰岛素信号和细胞凋亡中起着十分重要的作用.     

PAT家族蛋白在细胞内脂滴代谢过程中的作用

哺乳动物细胞内的甘油三酯是以脂滴的形式贮存的,现在有很多证据表明,脂滴参与多种代谢过程,因而被看作胞内有功能的细胞器。脂滴含有甘油三酯构成的脂质核心,脂核表面覆盖有单层磷脂,在单层磷脂内镶嵌着在结构上具有相关性的PAT家族蛋白,包括perilipin、ADRP、TIP47和S3—12。本文就这些蛋白在甘油三酯水解和脂滴合成中的调节作用加以综述。     

浅谈脂滴的发育和动员

长期认为脂滴是一种惰性结构,逐渐发现表明,脂滴是一种动态结构,负责脂质储存和能量代谢。本文对脂滴的发育、代谢、功能做一综述。     

The contribution of the Drosophila model to lipid droplet research

Intracellular lipid droplets have long been misconceived as evolutionarily conserved but functionally frugal components of cellular metabolism. An ever-growing repertoire of functions has elevated lipid droplets to fully-fledged cellular organelles. Insights into the multifariousness of these organelles have been obtained from a range of model systems now employed for lipid droplet research including the fruit fly, Drosophila melanogaster. This review summarizes the progress in fly lipid droplet research along four main avenues: the role of lipid droplets in fat storage homeostasis, the control of lipid droplet structure, the lipid droplet surface as a dynamic protein-association platform, and lipid droplets as mobile organelles. Moreover, the research potential of the fruit fly model is discussed with respect to the prevailing general questions in lipid droplet biology.     

Biogenesis of lipid droplets – how cells get fatter

Abstract

Lipid droplets are discrete organelles present in most cell types and organisms including bacteria, yeast, plants, insects and animals. Long considered as passive storage deposits, recent cell biology, proteomic and lipidomic analysis show that lipid droplets are dynamic organelles involved in multiple cellular functions. They have a central function in lipid distribution to different membrane-bound organelles and serve not only as main reservoirs of neutral lipids such as triglycerides and cholesterol but in addition, contain structural proteins, proteins involved in lipid synthesis and transmembrane proteins. A detailed model for how transmembrane proteins such as SNARE proteins can exist in lipid droplets is proposed.     

脂滴——细胞脂类代谢的细胞器

脂滴是细胞内中性脂贮存的主要场所,由极性单磷脂层包裹疏水核心组成。近年来的蛋白质组学研究表明,脂滴表面还存在着许多功能蛋白,进一步揭示了脂滴可能参与细胞内物质的代谢和转运,以及细胞信号传导等过程,是一个活动旺盛的多功能细胞器。实验结果还证明,脂滴不但是甘油三酯贮存和分解、花生四烯酸代谢和前列腺素合成的主要场所,脂滴还具有合成甘油三酯和磷酯的功能。由此可见,脂滴可能是细胞内参与脂类合成代谢的细胞器。     

The intracellular pathogen Orientia tsutsugamushi responsible for scrub typhus induces lipid droplet formation in mouse fibroblasts

Mammalian cells store excess fatty acids in the form of triglycerides within lipid droplets. The intracellular bacterium Orientia tsutsugamush is the causative agent of severe human rickettiosis. We found that O. tsutsugamushi infection induces the formation of lipid droplets in mouse L-929 fibroblasts. In infected cells, a parallel increase in the number of lipid droplets and pathogens was observed. Interestingly, the pathogen-infection induced the accumulation of triglycerides even without external supply of fatty acids. These results suggest that O. tsutsugamushi alters lipid metabolism of host cells to induce lipid droplets.     

Increased lipid droplet accumulation associated with a peripheral sensory neuropathy

Hereditary sensory neuropathy type 1 (HSN-1) is an autosomal dominant neurodegenerative disease caused by missense mutations in the SPTLC1 gene. The SPTLC1 protein is part of the SPT enzyme which is a ubiquitously expressed, critical and thus highly regulated endoplasmic reticulum bound membrane enzyme that maintains sphingolipid concentrations and thus contributes to lipid metabolism, signalling, and membrane structural functions. Lipid droplets are dynamic organelles containing sphingolipids and membrane bound proteins surrounding a core of neutral lipids, and thus mediate the intracellular transport of these specific molecules. Current literature suggests that there are increased numbers of lipid droplets and alterations of lipid metabolism in a variety of other autosomal dominant neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. This study establishes for the first time, a significant increase in the presence of lipid droplets in HSN-1 patient-derived lymphoblasts, indicating a potential connection between lipid droplets and the pathomechanism of HSN-1. However, the expression of adipophilin (ADFP), which has been implicated in the regulation of lipid metabolism, was not altered in lipid droplets from the HSN-1 patient-derived lymphoblasts. This appears to be the first report of increased lipid body accumulation in a peripheral neuropathy, suggesting a fundamental molecular linkage between a number of neurodegenerative diseases.     

Transport and Retention Mechanisms Govern Lipid Droplet Inheritance in Saccharomyces cerevisiae

Lipid droplets are ubiquitous cellular structures involved in energy homeostasis and metabolism that have long been considered as simple inert deposits of lipid. Here, we show that lipid droplets are bona fide organelles that are actively partitioned between mother cell and daughter cell in Saccharomyces cerevisiae. Video microscopy revealed that a subset of lipid droplets moves from mother cell to bud in an ordered, vectorial process, while the remaining lipid droplets are retained by the mother cell. Bud‐directed movement of lipid droplets is mediated by the molecular motor Myo2p, while retention of lipid droplets occurs at the perinuclear endoplasmic reticulum. Lipid droplets are thus apportioned between mother cell and daughter cell at cell division rather than being made anew.      

Dengue Virus Capsid Protein Usurps Lipid Droplets for Viral Particle Formation

Dengue virus is responsible for the highest rates of disease and mortality among the members of the Flavivirus genus. Dengue epidemics are still occurring around the world, indicating an urgent need of prophylactic vaccines and antivirals. In recent years, a great deal has been learned about the mechanisms of dengue virus genome amplification. However, little is known about the process by which the capsid protein recruits the viral genome during encapsidation. Here, we found that the mature capsid protein in the cytoplasm of dengue virus infected cells accumulates on the surface of ER-derived organelles named lipid droplets. Mutagenesis analysis using infectious dengue virus clones has identified specific hydrophobic amino acids, located in the center of the capsid protein, as key elements for lipid droplet association. Substitutions of amino acid L50 or L54 in the capsid protein disrupted lipid droplet targeting and impaired viral particle formation. We also report that dengue virus infection increases the number of lipid droplets per cell, suggesting a link between lipid droplet metabolism and viral replication. In this regard, we found that pharmacological manipulation of the amount of lipid droplets in the cell can be a means to control dengue virus replication. In addition, we developed a novel genetic system to dissociate cis-acting RNA replication elements from the capsid coding sequence. Using this system, we found that mislocalization of a mutated capsid protein decreased viral RNA amplification. We propose that lipid droplets play multiple roles during the viral life cycle; they could sequester the viral capsid protein early during infection and provide a scaffold for genome encapsidation.     

Rab32 is important for autophagy and lipid storage in Drosophila

Lipids are essential components of all organisms. Within cells, lipids are mainly stored in a specific type of organelle, called the lipid droplet. The molecular mechanisms governing the dynamics of lipid droplets have been little explored. The protein composition of lipid droplets has been analyzed in numerous proteomic studies, and a large number of lipid droplet-associated proteins have been identified, including Rab small GTPases. Rab proteins are known to participate in many intracellular membranous events; however, their exact role in lipid droplets is largely unexplored. Here we systematically investigate the roles of Drosophila Rab family proteins in lipid storage in the larval adipose tissue, fat body. Rab32 and several other Rabs were found to affect the size of lipid droplets as well as lipid levels. Further studies showed that Rab32 and Rab32 GEF/Claret may be involved in autophagy, consequently affecting lipid storage. Loss-of-function mutants of several components in the autophagy pathway result in similar effects on lipid storage. These results highlight the potential functions of Rabs in regulating lipid metabolism.