LDs (lipid droplets) carrying TAG (triacylglycerol) and cholesteryl esters are emerging as dynamic cellular organelles that are generated in nearly every cell. They play a key role in lipid and membrane homoeostasis. Abnormal LD dynamics are associated with the pathophysiology of many metabolic diseases, such as obesity, diabetes, atherosclerosis, fatty liver and even cancer. Chylomicrons, stable droplets also consisting of TAG and cholesterol are generated in the intestinal epithelium to transport exogenous (dietary) lipids after meals from the small intestine to tissues for degradation. Defective chylomicron formation is responsible for inherited lipoprotein deficiencies, including abetalipoproteinaemia, hypobetalipoproteinaemia and chylomicron retention disease. These are disorders sharing characteristics such as fat malabsorption, low levels of circulating lipids and fat-soluble vitamins, failure to thrive in early childhood, ataxic neuropathy and visual impairment. Thus understanding the molecular mechanisms governing the dynamics of LDs and chylomicrons, namely, their biogenesis, growth, maintenance and degradation, will not only clarify their molecular role, but might also provide additional indications to treatment of metabolic diseases. In this review, we highlight the role of two small GTPases [ARFRP1 (ADP-ribosylation factor related protein 1) and ARL1 (ADP-ribosylation factor-like 1)] and their downstream targets acting on the trans-Golgi (Golgins and Rab proteins) on LD and chylomicron formation.
Background: Abnormalities in lipid metabolism and lipoprotein and lipid droplet (LD) formation can lead to dyslipidaemia, fatty liver disease and type 2 diabetes. Lipoprotein and LD synthesis are initiated in the ER, further maturation occurs in the Golgi apparatus. We have recently shown that deletion of GTPase ARFRP1 in the intestinal epithelium results in impaired chylomicron (CM) formation. ARFRP1 recruits ARL1 and Golgins, that interact with several Rab GTPases to the trans-Golgi and is thereby involved in cellular trafficking events. The aim was to clarify the mechanisms involved in the lipidation and release of CMs.
The uptake and processing of dietary lipids by the small intestine is a multistep process that involves several steps including vesicular and protein transport. The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) controls the ARF-like 1 (ARL1)-mediated Golgi recruitment of GRIP domain proteins which in turn bind several Rab-GTPases. Here, we describe the essential role of ARFRP1 and its interaction with Rab2 in the assembly and lipidation of chylomicrons in the intestinal epithelium. Mice lacking Arfrp1 specifically in the intestine (Arfrp1(vil-/-)) exhibit an early post-natal growth retardation with reduced plasma triacylglycerol and free fatty acid concentrations. Arfrp1(vil-/-) enterocytes as well as Arfrp1 mRNA depleted Caco-2 cells absorbed fatty acids normally but secreted chylomicrons with a markedly reduced triacylglycerol content. In addition, the release of apolipoprotein A-I (ApoA-I) was dramatically decreased, and ApoA-I accumulated in the Arfrp1(vil-/-) epithelium, where it predominantly co-localized with Rab2. The release of chylomicrons from Caco-2 was markedly reduced after the suppression of Rab2, ARL1 and Golgin-245. Thus, the GTPase ARFRP1 and its downstream proteins are required for the lipidation of chylo-microns and the assembly of ApoA-I to these particles in the Golgi of intestinal epithelial cells.
Background/Aim: Circulating adiponectin, which has insulin sensitizing effects on liver and muscle, is synthesized at the endoplasmic reticulum and proceeds through compartments of the Golgi apparatus prior to its secretion into the bloodstream. We have recently observed that postnatal adipocyte-specific deletion of the trans-Golgi associated GTPase ARFRP1 (ADP-ribosylation factor-related Protein1), which is required for organizing specific protein scaffolds in this compartment, resulted in elevated blood glucose levels and increased hepatic glucose production in the absence of ectopic fat storage. We therefore aim to elucidate the detailed machanism of ARFRP1 and its downstream effectors in regulating adipocyte secretory function.
Background: An adequate lipid homeostasis involving storage and distribution of lipids is crucial as disturbances contribute to fatty liver disease, type 2 diabetes and atherosclerosis. Dietary lipids are absorbed by the intestine and packed in chylomicrons (CM) for distribution. In the liver, lipids are either stored in cytoplasmic lipid droplets (LD) or secreted as very low density lipoproteins (VLDL). Generation of LD and VLDL/CM is initiated in the endoplasmic reticulum, followed by lipidation at the Golgi. Our aim was to clarify the role of Golgi-associated proteins in LD and VLDL/CM formation. ADP-ribosylation factor-related protein 1 (ARFRP1) is a small trans-Golgi associated GTPase that is involved in protein sorting by acting upstream of a golgin scaffolding complex.
