Rab proteins implicated in lipid storage and mobilization

Abstract

Abnormal intracellular accumulation or transport of lipids contributes greatly to the pathogenesis of human diseases. In the liver, excess accumulation of triacylglycerol (TG) leads to fatty liver disease encompassing steatosis, steatohepatitis and fibrosis. This places individuals at risk of developing cirrhosis, hepatocellular carcinoma or hepatic decompensation and also contributes to the emergence of insulin resistance and dyslipidemias affecting many other organs. Excessive accumulation of TG in adipose tissue contributes to insulin resistance as well as to the release of cytokines attracting leucocytes leading to a pro-inflammatory state. Pathological accumulation of cholesteryl ester (CE) in macrophages in the arterial wall is the progenitor of atherosclerotic plaques and heart disease. Overconsumption of dietary fat, cholesterol and carbohydrates explains why these diseases are on the increase yet offers few clues for how to prevent or treat individuals. Dietary regimes have proven futile and barring surgery, no realistic alternatives are at hand as effective drugs are few and not without side effects. Overweight and obesity-related diseases are no longer restricted to the developed world and as such, constitute a global problem. Development of new drugs and treatment strategies are a priority yet requires as a first step, elucidation of the molecular pathophysiology underlying each associated disease state. The lipid droplet (LD), an up to now overlooked intracellular organelle, appears at the heart of each pathophysiology linking key regulatory and metabolic processes as well as constituting the site of storage of both TGs and CEs. As the molecular machinery and mechanisms of LDs of each cell type are being elucidated, regulatory proteins used to control various cellular processes are emerging. Of these and the subject of this review, small GTPases belonging to the Rab protein family appear as important molecular switches used in the regulation of the intracellular trafficking and storage of lipids.

Triglyceride Mobilization from Lipid Droplets Sustains the Anti-Steatotic Action of Iodothyronines in Cultured Rat Hepatocytes

“…Treatment with iodothyronines induced a decrease in the expression of both Rab18 and TIP47. Rab18 is a LD-coating GTPase, whose role in lipid metabolism is still under debate, but it seems to be involved in basal lipogenesis and TAG accumulation (Kiss and Nilsson, 2014 ). Recently, several Rab proteins have been localized to LD surface, and some works revealed that GTP is a key mediator of LD-mitochondria interaction.…”

“…Rab proteins, as key regulators of membrane trafficking, are involved in LD interactions (Murphy et al, 2009 ). Among the Rab family, LD-associated Rab18 plays a crucial role in the vesicle trafficking between LDs and other organelles (such as mitochondria, peroxisomes, endoplasmic reticulum (ER)) and regulates LD quantity and diameter by controlling fusion/fission processes (Stenmark, 2009 ; Kiss and Nilsson, 2014 ). It is now accepted that storage and release of FFAs from LDs result from variations in the expression and/or activity of PLIN proteins and associated lipases.…”

Characterization of the Proteome of Cytoplasmic Lipid Droplets in Mouse Enterocytes after a Dietary Fat Challenge

“…This consistent observation has not been fully investigated and remains an intriguing paradox of CLD biology. Several hypotheses have been proposed to address this issue including the role of CLDs as sequestration sites [ 59 , 60 ] or in the regulation of membrane trafficking [ 61 ]. The identification of non-lipid related protein in the CLD fraction has expanded our perception of the CLD from a simple lipid storage site to a complex and multi-functional organelle [ 62 ].…”

Persimmon vinegar ripening with the mountain-cultivated ginseng ingestion reduces blood lipids and lowers inflammatory cytokines in obese adolescents

“…Regarding the decreasing rate among the groups, PV and MPV had more significant decrease than CON; while there was no difference between PV and MPV. The reason is believed to be the decrease in body fat quantity and blood lipid in PV and MPV, in the view of existing studies as follows: the increase in cytokine secretion by excessive storage of body fat [ 60 ] and the decrease in proinflammatory cytokine secretion accompanied by the decrease in blood triglyceride [ 61 ].…”