Cideb, an ER- and Lipid Droplet-Associated Protein, Mediates VLDL Lipidation and Maturation by Interacting with Apolipoprotein B

Abstract

Secretion of triacylglycerol-enriched very-low-density lipoproteins (VLDLs) from the liver is vital for maintaining plasma lipid homeostasis. However, the process of VLDL assembly and lipidation is not well characterized. Here, we observed that liver of Cideb null mice had higher levels of triacylglycerols accompanied by low level of VLDL secretion. Furthermore, VLDL particles secreted from hepatocytes of Cideb null mice have low levels of triacylglycerols but normal levels of apoB. We also observed that Cideb is localized to endoplasmic reticulum and lipid droplets. Importantly, we have identified apoB as a Cideb-interacting protein. By infecting adenoviruses expressing various Cideb truncations into hepatocytes of Cideb null mice, we found that Cideb requires both its apoB-binding and lipid droplet association domains to restore the secretion of triacylglycerol-enriched VLDL particles. Our data suggest that Cideb promotes the formation of triacylglycerol-enriched VLDL particles and provides a molecular insight into VLDL lipidation and maturation in hepatocytes.

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…Among CIDE proteins, Cideb promotes the formation of TG-enriched VLDL particles and provides a molecular insight into VLDL lipidation and maturation in hepatocytes (Ye et al, 2009). Cideb deficiency results in lower plasma TGs and FA levels , thereby suggesting a potential role for Cideb in the development of atherosclerosis.…”

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

“…Ectopically expressed CIDEA-eGFP localized to lipid droplets in 3T3-L1 adipocytes and COS cells and endogenous CIDEA protein is found at lipid droplets of cultured human white adipocytes and cultured murine brown adipocytes (26). Most recently, ectopically expressed CIDEB was shown to be localized to lipid droplets of lipid-loaded hepatocytes and the regions of the CIDEB protein that governed lipid droplet localization examined (42). Ectopic expression of an HA-tagged or eGFP fusion construct containing amino acids 166 -195 of CIDEB was sufficient for lipid droplet targeting in lipid-loaded COS cells and HepG2 hepatocytes, respectively (42).…”

“…Ectopic expression of an HA-tagged or eGFP fusion construct containing amino acids 166 -195 of CIDEB was sufficient for lipid droplet targeting in lipid-loaded COS cells and HepG2 hepatocytes, respectively (42). CIDEA and CIDEB are also reportedly localized to the endoplasmic reticulum, an organelle from which biogenesis of intracellular lipid droplets initiates (27,42). Moreover, in addition to being lipid droplet-localized proteins per se, ectopic expression of FSP27 and CIDEA has been demonstrated to promote the formation and/or enlargement of lipid droplets in several nonadipocyte cell types, a phenomenon that is particularly evident with addition of exogenous oleic acid to culture media.…”

“…However, recent studies strongly suggest that this localization was incorrect and that FSP27, CIDEA, and CIDEB are lipid droplet-associated proteins (12,21,25,33,42). Signal for an FSP27-enhanced green fluorescent protein (eGFP) fusion protein has been shown to be colocalized to lipid droplets in 3T3-L1 adipocytes and lipid-loaded 293T cells (12).…”

“…Most recently, ectopically expressed CIDEB was shown to be localized to lipid droplets of lipid-loaded hepatocytes and the regions of the CIDEB protein that governed lipid droplet localization examined (42). Ectopic expression of an HA-tagged or eGFP fusion construct containing amino acids 166 -195 of CIDEB was sufficient for lipid droplet targeting in lipid-loaded COS cells and HepG2 hepatocytes, respectively (42). CIDEA and CIDEB are also reportedly localized to the endoplasmic reticulum, an organelle from which biogenesis of intracellular lipid droplets initiates (27,42).…”