Very-low-density lipoproteins (VLDLs) are synthesized in the liver and play an important role in the pathogenesis of atherosclerosis. Transport of VLDL from its site of synthesis, the endoplasmic reticulum (ER) to the Golgi in primary hepatocytes is prerequisite for its eventual secretion from the hepatocyte and represents a potential therapeutic target in controlling elevated concentrations of its metabolite LDL, the major carrier of cholesterol and determinant of atherosclerosis. Our laboratory is focused on deciphering the intracellular itinerary of VLDL and its regulation in primary hepatocytes.
Our data indicate that VLDL and albumin (a typical liver secretory protein) are transported separately in two different vesicles from the liver ER to the Golgi. We found that despite the two cargoes being transported in different vesicles, both types of vesicles utilize the same initiator of ER vesicle budding, Sar1, a component of the coat protein complex II (COPII). We have identified a specialized vesicle, the VLDL transport vesicle (VTV), which mediates the ER-to-Golgi transport of VLDL in hepatocytes. Our electron microscopic data revealed that VTVs are larger (~100-120 nm) than albumin carrying vesicles (referred as COPII vesicles; ~55-70 nm) in order to accommodate their larger cargo, the VLDL. We hypothesize that different proteins are involved with the selection of cargo for each of the two types of transport vesicles. Currently, we are involved in identifying proteins regulating ER-to-Golgi transport of VLDL in primary hepatocytes.
- Shadab A. Siddiqi. In Vitro Analysis of the Very-low Density Lipoprotein Export from the Trans-Golgi Network. Current Protocols in Cell Biology (2015) 67:11.21.1-17
- Hossain T, Riad A, Siddiqi S, Parthasarathy S and Shadab A. Siddiqi. Mature VLDL Triggers the Biogenesis of a Distinct Vesicle from the Trans Golgi Network for its Export to the Plasma Membrane. Biochem J. (2014) Apr 1;459(1):47-58.
- Samata Tiwari, Shaila Siddiqi, and Shadab A. Siddiqi. CideB Protein is Required for the Biogenesis of Very Low-density Lipoprotein (VLDL) Transport Vesicle. J Biol Chem. (2013); 288(7): 5157-65.
- Shukur M, Tiwari S, Sankpal U, Shadab A. Siddiqi and Basha Riyaz. Tolfenamic acid Suppresses Cytochrome P450 2E1 Expression in Mouse Liver. Integrative Biology (2012) 4:1122-1129.
- Abdul Rahim, Erika Nafi-valencia, Shaila Siddiqi, Riyaz Basha, C. Carl Runyon and Shadab A. Siddiqi. Proteomic Analysis of VLDL Transport Vesicle (VTV). J Proteomics (2012) 75:2225-2235.
- Samata Tiwari and Shadab A. Siddiq. Intracellular Trafficking and VLDL Secretion. Arteriosclerosis,Thrombosis, and Vascular Biology (ATVB) (2012) 32(5):1079-86.
- Bhaswati Sengupta and Shadab A. Siddiqi. Hepatocellular carcinoma: Important Biomarkers and Their Significance in Molecular Diagnostics and Therapy. Current Molecular Medicine (2012);19:1-8.
- Samata Tiwari and Shadab A. Siddiqi. Intracellular Trafficking and VLDL Secretion. Arteriosclerosis,Thrombosis, and Vascular Biology (ATVB) (2012); 32(5):1079-86.
- Abdul Rahim, Erika Nafi-valencia, Shaila Siddiqi, Riyaz Basha, C. CarlRunyon and Shadab A. Siddiqi. Proteomic Analysis of VLDL Transport Vesicle (VTV). J Proteomics (2012); 75:2225-2235. doi: 10.1016/j.jprot.2012.01.026.
- Bhaswati Sengupta and Shadab A. Siddiqi. Hepatocellular carcinoma: Important Biomarkers and Their Significance in Molecular Diagnostics and Therapy. Current Molecular Medicine (2012); 19:1-8. (In press)
- Shaila Siddiqi, Arul M. Mani and Shadab A Siddiqi. The Identification of the SNARE-complex Required for the Fusion of VLDL Transport Vesicle with Hepatic cis-Golgi. Biochem J. (2010) 429(2):391-401.
- Charles M. Mansbach II and Shadab A. Siddiqi. The Biogenesis of Chylomicrons. Annual Review of Physiology (2010) Vol. 72, 315-333.
- Siddiqi, Shahzad, Shadab. A. Siddiqi and Charles M. Mansbach II. SEC24C is required for the docking of the pre-chylomicron transport vesicle with the Golgi. J. Lipid Res. (2010) May;51(5):1093-100.
- Siddiqi S, Saleem U, Abumrad N, Davidson N, Storch J, Siddiqi SA, Mansbach CM 2nd. A Novel Multi-protein Complex Is Required for the Generation of thePre-chylomicron Transport Vesicle from Intestinal ER. J Lipid Res. (2010) Mar 17. 51(7):1918-28.
- Yellaturu CR , Deng X, Cagen LM, Mansbach CM, Siddiqi SA, Park EA, Raghow R, Elam MB. Insulin enhances posttranslational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J. Biol. Chem. (2009) 284(12):7518-32.
- Shadab A. Siddiqi. VLDL exits from the endoplasmic reticulum in a specialized vesicle, the VLDL- transport vesicle in rat primary hepatocytes. Biochem J. (2008) 413(2): 333-342.
- Shadab. A. Siddiqi and Charles. M. Mansbach II. PKCz Mediated Phosphorylation Controls the Budding of the Pre-Chylomicron Transport Vesicle. J. Cell Sci. (2008) 121:2327-38.