The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL

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 (1α and 1β), -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-1α or -1β increased the synthesis and secretion of [3H]glycerol-labeled lipids under either basal- or oleate-supplemented conditions. In the presence of oleate, the increased TAG secretion was mainly associated with VLDL1 (Sf > 100) and VLDL2 (Sf 20–100). Expression of lipin-1α or -1β increased secretion efficiency and decreased intracellular degradation of [35S]apolipoprotein B-100 (apoB100). Knockdown of lipin-1 using specific short interfering RNA decreased secretion of [3H]glycerolipids and [35S]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-1α not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1α mutant failed to promote [35S]apoB100 synthesis or secretion, and showed compromised stimulation in [3H]TAG synthesis and secretion. Thus, alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion. 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 (1α and 1β), -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-1α or -1β increased the synthesis and secretion of [3H]glycerol-labeled lipids under either basal- or oleate-supplemented conditions. In the presence of oleate, the increased TAG secretion was mainly associated with VLDL1 (Sf > 100) and VLDL2 (Sf 20–100). Expression of lipin-1α or -1β increased secretion efficiency and decreased intracellular degradation of [35S]apolipoprotein B-100 (apoB100). Knockdown of lipin-1 using specific short interfering RNA decreased secretion of [3H]glycerolipids and [35S]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-1α not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1α mutant failed to promote [35S]apoB100 synthesis or secretion, and showed compromised stimulation in [3H]TAG synthesis and secretion. Thus, alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion. The major lipoproteins carrying triacylglycerol (TAG) in fasted human plasma are VLDL that are synthesized by the liver. Formation of hepatic VLDL requires the active synthesis of various lipid constituents (e.g., TAG, cholesterol, cholesteryl esters, and phospholipids) that are assembled together with the large, hydrophobic apolipoprotein B100 (apoB100) (1Fisher E.A Ginsberg H.N. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins..J. Biol. Chem. 2002; 277: 17377-17380Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 2Rustaeus S. Lindberg K. Stillemark P. Claesson C. Asp L. Larsson T. Boren J. Olofsson S.O. 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PubMed Scopus Google Scholar). short interfering specific for lipin-1 from McA-RH7777 cells in and with lipin-1 using or of to the The lipin-1 was of was for and for gene expression by The was with for lipin-1 with control which or with Cells after and to or for the Cell of of by and membranes. lipin-1 using In cells with for in and lipin-1 was by using and to and The activity in McA-RH7777 cells and was determined to M. J. M. Yao Z. K. Lehner R. D.N. and hepatic lipin-1 and Full Text Full Text PDF PubMed Scopus Google Scholar). Cells on in for Cells with for and with in for The cells with for and with A for with cells with with and with The using using a on an with for and the for was as Y. Tran K. Yao Z. The activity of microsomal triglyceride transfer protein is essential for accumulation of triglyceride within microsomes in McA-RH7777 cells. A unified model for the assembly of very low density lipoproteins..J. Biol. 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Cells with or as The was and the lipoproteins by to separate VLDL1 and VLDL2 from the lipoproteins Y. Tran K. Yao Z. The activity of microsomal triglyceride transfer protein is essential for accumulation of triglyceride within microsomes in McA-RH7777 cells. A unified model for the assembly of very low density lipoproteins..J. Biol. Chem. 1999; 274: 27793-27800Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). from lipoprotein and by The [35S]apoB100 was from lipoprotein by and by as Cells with for The and with and for to the of [35S]apoB100 and from and by and to and as Y. Tran K. Yao Z. The activity of microsomal triglyceride transfer protein is essential for accumulation of triglyceride within microsomes in McA-RH7777 cells. A unified model for the assembly of very low density lipoproteins..J. Biol. Chem. 1999; 274: 27793-27800Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). expressing cells in and and using a using a for the for activity protein as J. M.M. A and for microsomal triglyceride transfer 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, P. C. M.M. of cholesteryl and phospholipids as well as by microsomal triglyceride transfer 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of RNA from and by to using A as control M. J. M. Yao Z. K. Lehner R. D.N. and hepatic lipin-1 and Full Text Full Text PDF PubMed Scopus Google Scholar). The sequences for of are in are as The of control and cells was using was in the cells by the A and for the of of protein utilizing the of Biochem. PubMed Scopus Google Scholar). of lipin-1α or -1β into McA-RH7777 cells resulted in expression of the lipin-1 which in cell with the by using also the protein of PAP-1 activity using cell showed increased PAP-1 activity lipin-1 expression of of and lipin-1 that lipin-1α was in the and in the The efficiency of lipin-1 in cells was as determined by The contribution of lipin-1α and -1β to glycerolipid synthesis and secretion was determined by under or with conditions. of into and [3H]TAG as under was in lipin-1α and -1β cells of into the the of into TAG of for in the of [3H]TAG secretion from lipin-1α and -1β cells was increased as with of into and was also increased from lipin-1α and -1β cells in the presence of an in and was also in cells and increased of synthesis and secretion The increased secretion of [3H]TAG was with the from to not the of [3H]TAG and secretion from lipin-1α and -1β cells was that from control cells The of lipin-1 for glycerolipid synthesis and secretion was determined using a of McA-RH7777 cells with resulted in in lipin-1 protein and in the of lipin-1 to The of lipin-2 or -3 not by the lipin-1 The for -2, and -3 and during and the required to -2, and -3 and The of required for lipin-1 that lipin-1 the lipin in McA-RH7777 cells. The lipin-2 or -3 protein not owing to the of specific The PAP-1 showed that lipin-1 not the PAP-1 activity in the cells that lipin-1 expression in cells is low with that of lipin-2 and -3. lipin-1 secretion of [3H]glycerol-labeled TAG, and was by as determined by The secretion of [3H]glycerolipids was not to impaired as by of into TAG control and lipin-1 cells is with the of an effect of lipin-1 on total PAP-1 which is mainly by lipin-2 and -3. The effect of the on secretion to a specific role of lipin-1 in The lipoproteins from cells under and by to the association of [3H]glycerolipids with various The increased [3H]TAG secretion from lipin-1α and -1β cells was associated with VLDL1 (Sf > 100) VLDL2 (Sf the from cells was in and the in secretion was associated with VLDL The secretion of in association with lipoproteins was not by lipin expression secretion of in was it not the that de novo synthesis of and secretion as are increased by expression of lipin-1 of as a of increased of in cells. expression of lipin-1α or -1β resulted in increased of into and apoB100 as with with The effect of lipin-1α and -1β was specific to of into was A effect of lipin-1 expression on [35S]apoB100 secretion was cells in the of not of lipoproteins showed that the increased secretion of [35S]apoB100 from lipin-1α or -1β expressing cells was mainly associated with VLDL1 and VLDL2 The [3H]TAG and [35S]apoB100 that the of lipin-1α or -1β expression a major on the assembly and secretion of in McA-RH7777 cells. Knockdown of lipin-1 using resulted in decreased [35S]apoB100 in the cells and by as with the synthesis the secretion of was lipin-1 that the of lipin-1 expression in McA-RH7777 cells a on the synthesis and secretion of The for or or by lipin-1 into by which the of lipin-1 expression into to to the and secretion efficiency of synthesized the of the of into apoB100 in lipin-1α or -1β cells was to or that in control cells in The was was in the presence of the to apoB100 degradation in the of the the of into apoB100 in lipin-1α and cells was that in control cells are in with increased apoB100 accumulation in the cells lipin-1 expression We determined the secretion efficiency of apoB100 and to efficiency was as the of synthesized apoB100 during of [35S]apoB100 in cells and during are in the of C. of associated with [35S]apoB100 showed that the secretion efficiency of apoB100 and was increased from lipin-1α and -1β expressing cells as with to was for [3H]TAG secretion a effect lipin-1α on apoB100 secretion as the The apoB100 during was not by lipin-1α or -1β expression The of was not by lipin-1α or -1β was secretion efficiency not In where was in the the effect of on apoB100 secretion was of function during secretion of apoB100 from control cells was as as that from cells. that the increased apoB100 secretion efficiency in cells was to degradation of synthesized The effect on apoB100 secretion from and apoB100 secretion efficiency from cells was that from lipin-1α cells under The effect on apoB100 or not of lipid transfer activity of using cell showed that expression of lipin-1α or -1β in McA-RH7777 cells effect on not that expression of a effect on apoB100 secretion degradation of synthesized lipin-1α and -1β in the that on apoB100 secretion efficiency to compartmentalization of lipin-1 Thus, the function of lipin-1α in hepatic glycerolipid synthesis with that of a that the sequence of the into McA-RH7777 cells resulted in expression of the protein the protein its nuclear and in the the of nuclear localization of the mutant lipin-1α or the mutant the to with microsomal membranes and mainly cytosolic that the sequences not only nuclear localization but also association and function of The expression of increased PAP-1 activity to the as the lipin-1α showed that [3H]TAG and in expressing cells as with expressing the lipin-1α secretion of [3H]TAG and was also decreased from expressing cells as with lipin-1α as with expression of synthesis and secretion. that of the expression of failed to of into cell or Synthesis or secretion of was not by lipin-1α or expression that the localization of lipin-1α an on hepatic and apoB100 expression is a specific for by and in the and In and the expression of but not lipin-2 or a within the M. 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