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.
Highlights
Rab proteins are cytosolic small molecule GTPases that are recruited to the cytosolic leaflet of intracellular membranes where they function in various cellular processes
As Rab proteins have been implicated in the regulation of SNARE-dependent fusion events elsewhere in the cell, it is possible that the observed stimulatory role of Rab18 in fusion and fission of lipid droplet (LD) involves the regulation and recruitment of SNAREs and associated proteins[64]
This study demonstrated that cyclooxygenase-2 and 5-lipoxygenase were able to stimulate the Rab18 promoter through activating transcription factor activator protein 1 (AP-1) and cyclic adenosine 39,59-monophosphate response element-binding protein (CREB)
Summary
Rab proteins are cytosolic small molecule GTPases that are recruited to the cytosolic leaflet of intracellular membranes where they function in various cellular processes. This cycling between an ‘‘off’’ (RabGDP) and an ‘‘on’’ (RabGTP) state is accompanied by a conformational change that alters its interaction with effector and accessory molecules Apart from their role as molecular switches, Rab proteins can be viewed as macromolecular organizers regulating the assembly of protein complexes. Transition from the ‘‘off’’ (RabGDP) to the ‘‘on’’ (RabGTP) state is facilitated by a guanine nucleotide exchange factor (GEF) and coincides with the recruitment to its site of action, e.g. a specific membrane domain enabling the Rab protein to bind and assemble effector molecules for specific functions (e.g. membrane mobility, membrane fusion). Combined with affinity-based chromatography, such molecular approaches should prove useful in further elucidating the various processes involving Rab proteins and in the biochemical isolation of involved molecular complexes
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