Rab proteins as regulators of lipid droplet formation and lipolysis

Abstract

Lipid droplets (LDs) are highly dynamic organelles that not only store neutral lipids but also are involved in multiple cellular processes. Dysregulation of lipogenesis or lipolysis greatly contributes to the pathogenesis of several human diseases, including obesity, diabetes, and fatty liver disease. Rab proteins have been found to be associated with LDs in proteomic studies and are also known to extensively regulate intracellular membrane traffic, suggesting that LDs actively communicate with other membrane compartments to maintain energy homeostasis. This review discusses recent studies that provide mechanistic insights into the regulation of LD formation and catabolism by Rab proteins in mammalian cells.

A RasGAP, DAB2IP, regulates lipid droplet homeostasis by serving as GAP toward RAB40C

“…Proteomic analyses have identified proteins important in intracellular traffic such as small GTPases on LD surfaces [ 2 , 3 ]. Among them, Rab18 was the best characterized Rab protein functioning on LDs [ 4 - 11 ]. Recently, RAB40C was reported to be LD-associated.…”

An Overview of Lipid Droplets in Cancer and Cancer Stem Cells

“…These proteins seem to be entailed in trafficking and sequestration of proteins to LDs and in lipid mobilization from LDs with the aim at delivering them to different cellular compartments, at regulating their levels, and/or at hampering their binding with target partners [ 69 , 70 ]. In this context, Rab GTPases are the most abundant class of proteins associated to LDs, even though, only for some of them, such as Rab1, Rab5, Rab10, Rab18, and Rab32, a functional interaction with LDs has been reported [ 68 , 71 ]. Recent evidence also suggests a crucial role of SNARE proteins in the fusion of LDs and of Arf1/COP-I complex, which would allow ATGL to target LDs by inducing the dissociation of PLIN2 ( Figure 3 ) [ 25 , 68 ].…”

“…Therefore, LD-associated proteins are linked to both LD formation and interplay with other cytoplasmic organelles through complex pathways and, to date, the mechanisms involved in targeting and recruitment of the proteins from cytosol and ER onto LD surface, as well as the protein-specific contribution to LD homeostasis, remain to be elucidated. For a more exhaustive description of LD-associated proteins, we refer the readers to more detailed reviews [ 26 , 71 , 76 ].…”

Cellular endo‐lysosomal dysfunction in the pathogenesis of non‐alcoholic fatty liver disease

“…There are over 70 members of the Rab family of proteins, which are involved in almost all stages of vesicular transport, from vesicle budding and delivery to tethering to the vesicle membrane and target compartment fusion . Rab proteins have been associated with the dysregulation of lipogenesis or lipolysis, which greatly contributes to the pathogenesis of NAFLD . Rab8a plays a critical role in lipid droplet (LD) fusion and growth mediated by fat‐specific protein 27 (Fsp27), which is highly enriched at LD‐LD contact sites.…”

“…Rabl2 dysfunction leads to retarded hepatic mitochondrial movement and a cascading phenotype consisting of insulin resistance, glucose intolerance and hepatic steatosis, even in mice fed a low‐fat chow diet . In addition to those discussed above, many other Rab proteins (Rab1, Rab5, Rab7, Rab18, Rab32 and Rab40c) have been functionally linked with LDs . Although these Rab proteins extensively regulate LD formation and interaction with other subcellular organelles, there is no evidence that they are related to the pathogenesis of fatty liver disease.…”