Regulation of VLDL Transport and Secretion

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Secretion of very-low-density lipoprotein (VLDL) from the liver is tightly controlled by its complex intracellular transport events. Aberrant VLDL secretion causes imbalance in lipid homeostasis which is associated with many metabolic diseases such as hyperlipidemia, hepatic steatosis etc. Biogenesis of VLDLs occurs in hepatic endoplasmic reticulum (ER); however, their maturation occurs in the Golgi. We have characterized the ER-to- Golgi VLDL transport process that is unique to the liver and have identified key regulators of this step; however, the transport of mature VLDL from the TGN to the PM for its secretion remains to be studied at the molecular level. In Aim 1, we extend our ongoing studies of determining the regulatory aspects of ER-to-Golgi transport. We have shown that SVIP is required for VTV biogenesis from the ER and VLDL secretion from hepatocytes. Our preliminary studies suggest that SVIP gets phosphorylated during VTV biogenesis; however, a specific protein kinase that phosphorylates SVIP is not known. We propose to identify the specific protein kinase that phosphorylates SVIP in Aim 1. Because phosphorylation of SVIP is specifically associated with VTV biogenesis and thus VLDL secretion, identification of a specific protein kinase will provide a novel selective target in controlling VLDL secretion. In Aim 2 and Aim 3, we propose to delineate the molecular machinery that regulates the post-TGN trafficking of mature VLDL. Our preliminary data suggest that mature VLDLs are transported from the TGN to the PM in distinct transport vesicles, the post-Golgi VLDL transport vesicle (PG-VTV), which are morphologically and biochemically different from other TGN-derived protein transport vesicles (PTV). Since the PG-VTV is distinct in its size, cargo, buoyant density and protein composition, we hypothesize that proteins, not previously considered important in the TGN-to-PM transport, mediate VLDL-selection and PG-VTV formation. These proteins are postulated to be important for cargo-selection, vesicle biogenesis and PG-VTV fusion with PM. In Aim 2, we propose to identify cargo-selecting protein that is required for effective packaging of mature VLDL in PG-VTV. We recently reported that L-FABP is required for normal VLDL secretion; however, the underlying mechanism is not known. In Aim 3, we will define the role of L-FABP and RBP4 in VLDL secretion from the liver. The proposed studies will shed new molecular insights into the poorly understood process of how mature VLDL is selected into the PG-VTV and is being transported to the PM for its eventual secretion in the blood and link these processes to identify potential targets in controlling VLDL secretion.