title: The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.
abstract: Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG). PAP-1 activity is encoded by members of the lipin family, including lipin-1 (1alpha and 1beta), -2, and -3. We determined the effect of lipin-1 expression on the assembly and secretion of very low density lipoproteins (VLDL) using McA-RH7777 cells. Expression of lipin-1alpha or -1beta increased the synthesis and secretion of [(3)H]glycerol-labeled lipids under either basal- or oleate-supplemented conditions. In the presence of oleate, the increased TAG secretion was mainly associated with VLDL(1) (S(f) > 100) and VLDL(2) (S(f) 20-100). Expression of lipin-1alpha or -1beta increased secretion efficiency and decreased intracellular degradation of [(35)S]apolipoprotein B-100 (apoB100). Knockdown of lipin-1 using specific short interfering RNA decreased secretion of [(3)H]glycerolipids and [(35)S]apoB100 even though total PAP-1 activity was not decreased, owing to the presence of lipin-2 and -3 in the cells. Deletion of the nuclear localization signal sequences within lipin-1alpha not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1alpha mutant failed to promote [(35)S]apoB100 synthesis or secretion, and showed compromised stimulation in [(3)H]TAG synthesis and secretion. Thus, alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion.
authors.affiliation: Department of Biochemistry, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Maroun
authors.initials: M
authors.lastname: Bou Khalil
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Sundaram
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Zhang
authors.forename: Philip H
authors.initials: PH
authors.lastname: Links
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Raven
authors.forename: Boripont
authors.initials: B
authors.lastname: Manmontri
authors.forename: Meltem
authors.initials: M
authors.lastname: Sariahmetoglu
authors.forename: Khai
authors.initials: K
authors.lastname: Tran
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
authors.forename: Zemin
authors.initials: Z
authors.lastname: Yao