Coordinate Regulation of Lipogenesis, the Assembly and Secretion of Apolipoprotein B-containing Lipoproteins by Sterol Response Element Binding Protein 1

Abstract

Stable plasmid-driven expression of the liver-specific gene product cholesterol 7α-hydroxylase (7α-hydroxylase) was used to alter the cellular content of transcriptionally active sterol response element binding protein 1 (SREBP1). As a result of stable expression of 7α-hydroxylase, individual single cell clones expressed varying amounts of mature SREBP1 protein. These single cell clones provided an opportunity to identify SREBP1-regulated genes that may influence the assembly and secretion of apoB-containing lipoproteins. Our results show that in McArdle rat hepatoma cells, which normally do not express 7α-hydroxylase, plasmid-driven expression of 7α-hydroxylase results in the following: 1) a linear relationship between (i) the cellular content of mature SREBP1 and 7α-hydroxylase protein, (ii) the relative expression of 7α-hydroxylase mRNA and the mRNA's encoding the enzymes regulating fatty acid, i.e. acetyl-CoA carboxylase and sterol synthesis, i.e. HMG-CoA reductase, (iii) the relative expression of 7α-hydroxylase mRNA and microsomal triglyceride transfer protein mRNA, a gene product that is essential for the assembly and secretion of apoB-containing lipoproteins; 2) increased synthesis of all lipoprotein lipids (cholesterol, cholesterol esters, triglycerides, and phospholipids); and 3) increased secretion of apoB100 without any change in apoB mRNA. Cells expressing 7α-hydroxylase contained significantly less cholesterol (both free and esterified). The increased cellular content of mature SREBP1 and increased secretion of apoB100 were concomitantly reversed by 25-hydroxycholesterol, suggesting that the content of mature SREBP1, known to be decreased by 25-hydroxycholesterol, mediates the changes in the lipoprotein assembly and secretion pathway that are caused by 7α-hydroxylase. These data suggest that several steps in the assembly and secretion of apoB-containing lipoproteins by McArdle hepatoma cells may be coordinately linked through the cellular content of mature SREBP1. Stable plasmid-driven expression of the liver-specific gene product cholesterol 7α-hydroxylase (7α-hydroxylase) was used to alter the cellular content of transcriptionally active sterol response element binding protein 1 (SREBP1). As a result of stable expression of 7α-hydroxylase, individual single cell clones expressed varying amounts of mature SREBP1 protein. These single cell clones provided an opportunity to identify SREBP1-regulated genes that may influence the assembly and secretion of apoB-containing lipoproteins. Our results show that in McArdle rat hepatoma cells, which normally do not express 7α-hydroxylase, plasmid-driven expression of 7α-hydroxylase results in the following: 1) a linear relationship between (i) the cellular content of mature SREBP1 and 7α-hydroxylase protein, (ii) the relative expression of 7α-hydroxylase mRNA and the mRNA's encoding the enzymes regulating fatty acid, i.e. acetyl-CoA carboxylase and sterol synthesis, i.e. HMG-CoA reductase, (iii) the relative expression of 7α-hydroxylase mRNA and microsomal triglyceride transfer protein mRNA, a gene product that is essential for the assembly and secretion of apoB-containing lipoproteins; 2) increased synthesis of all lipoprotein lipids (cholesterol, cholesterol esters, triglycerides, and phospholipids); and 3) increased secretion of apoB100 without any change in apoB mRNA. Cells expressing 7α-hydroxylase contained significantly less cholesterol (both free and esterified). The increased cellular content of mature SREBP1 and increased secretion of apoB100 were concomitantly reversed by 25-hydroxycholesterol, suggesting that the content of mature SREBP1, known to be decreased by 25-hydroxycholesterol, mediates the changes in the lipoprotein assembly and secretion pathway that are caused by 7α-hydroxylase. These data suggest that several steps in the assembly and secretion of apoB-containing lipoproteins by McArdle hepatoma cells may be coordinately linked through the cellular content of mature SREBP1. Apolipoprotein B100 (apoB) 1The abbreviations used are: apoB, apolipoprotein B; 7α-hydroxylase, cholesterol 7α-hydroxylase NADPH:oxygen oxidoreductase(EC 1.14.13.17); MTP, microsomal triglyceride transfer protein; SREBP, sterol response element binding protein; DMEM, Dulbecco's modified Eagle's medium; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, PAGE, polyacrylamide gel electrophoresis; LDL, low density lipoprotein; VLDL, very low density lipoprotein; BSA, bovine serum albumin. is an unusually large (>500 kDa) amphipathic protein responsible for the assembly and secretion of plasma lipoproteins by the liver and intestine (reviewed in Refs. 1Davis R.A. Vance J. Vance D.E. Vance J. New Comprehensive Biochemistry. 31. Elsevier Science Publishers B.V., Amsterdam1996: 473-494Google Scholar, 2Innerarity T.L. Boren J. Yamanaka S. Olofsson S.-O. J. Biol. Chem. 1996; 271: 2353-2356Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 3Dixon J.L. Ginsberg H.N. J. Lipid Res. 1993; 34: 167-179Abstract Full Text PDF PubMed Google Scholar). Its concentration in plasma, as a component of LDL, is a major determinant of susceptibility to the development of atherosclerotic cardiovascular disease (4Witztum J.L. Steinberg D. J. Clin. Invest. 1991; 88: 1785-1792Crossref PubMed Scopus (2474) Google Scholar, 5Berliner J.A. Navab M. Fogelman A.M. Frank J.S. Demer L.L. Edwards P.A. Watson A.D. Lusis A.J. Circulation. 1995; 91: 2488-2496Crossref PubMed Scopus (1593) Google Scholar). Hepatic derived apoB100-containing lipoproteins are the precursors of plasma LDL (6Kane J.P. Annu. Rev. Physiol. 1983; 45: 637-650Crossref PubMed Scopus (212) Google Scholar). Hepatic assembly and secretion of apoB-containing lipoproteins require an orchestration of many seemingly independent processes as follows: 1) the production of component lipids (cholesterol, cholesterol esters, triglycerides, and phospholipids); 2) the synthesis of apoB, a uniquely large polypeptide containing multiple amphipathic structural domains that irreversibly associate with phospholipids (7Segrest J.P. Jones M.K. Mishra V.K. Anantharamaiah G.M. Garber D.W. Arterioscler. Thromb. 1994; 14: 1674-1685Crossref PubMed Scopus (169) Google Scholar); 3) translocation across the endoplasmic reticulum that requires an intralumenal protein complex consisting of MTP and PDI (8Gordon D.A. Wetterau J.R. Gregg R.E. Trends Cell Biol. 1995; 5: 317-321Abstract Full Text PDF PubMed Scopus (120) Google Scholar); and 4) the assembly of VLDL particle within the endoplasmic reticulum (1Davis R.A. Vance J. Vance D.E. Vance J. New Comprehensive Biochemistry. 31. Elsevier Science Publishers B.V., Amsterdam1996: 473-494Google Scholar, 2Innerarity T.L. Boren J. Yamanaka S. Olofsson S.-O. J. Biol. Chem. 1996; 271: 2353-2356Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 9Ginsberg H.N. Curr. Opin. Lipidol. 1995; 6: 275-280Crossref PubMed Scopus (72) Google Scholar). Previous studies showed a coordinate induction of the synthesis of all VLDL lipids and the assembly and secretion of apoB-containing lipoproteins in response to changes in metabolic state (e.g.during dietary carbohydrate overload (10Boogaerts J.R. Malone M.M. Archambault S.J. Davis R.A. Am. J. Physiol. 1984; 246: E77-E83Crossref PubMed Google Scholar) and fetal development (11Coleman R.A. Haynes E.B. Sand T.M. Davis R.A. J. Lipid Res. 1988; 29: 33-42Abstract Full Text PDF PubMed Google Scholar)). In contrast, fasting caused a coordinate repression of all of these processes (12Davis R.A. Boogaerts J.R. Borchardt R.A. Malone-McNeal M. Archambault-Schexnayder J. J. Biol. Chem. 1985; 260: 14137-14144Abstract Full Text PDF PubMed Google Scholar, 13Leighton J.K. Joyner J. Zamarripa J. Deines M. Davis R.A. J. Lipid Res. 1990; 31: 1663-1668Abstract Full Text PDF PubMed Google Scholar). These findings led us to propose that in a coordinate manner, metabolic signals control multiple steps of the VLDL assembly/secretion pathway. Using a somatic cell genetic approach, we examined this possibility. Previous experiments showed that expression of the liver-specific gene 7α-hydroxylase (EC 1.14.13.17) in non-hepatic Chinese hamster ovary cells increased the transcription of the LDL receptor gene (14Dueland S. Trawick J.D. Nenseter M.S. MacPhee A.A. Davis R.A. J. Biol. Chem. 1992; 267: 22695-22698Abstract Full Text PDF PubMed Google Scholar), a process now known to be regulated by the SREBP family of transcription factors (15Briggs M.R. Yokoyama C. Wang X. Brown M.S. Goldstein J.L. J. Biol. Chem. 1993; 268: 14490-14496Abstract Full Text PDF PubMed Google Scholar, 16Wang X. Briggs M.R. Hua X. Yokoyama C. Goldstein J.L. Brown M.S. J. Biol. Chem. 1993; 268: 14497-14504Abstract Full Text PDF PubMed Google Scholar). Sterol-responsive transcriptional regulation is invoked by a proteolytic cleavage of the initial translational SREBP gene product that resides in the endoplasmic reticulum membrane as a trans-membrane loop X. Brown M.S. Hua X. Goldstein J.L. 1994; Full Text PDF PubMed Scopus Google Scholar, J. Hua X. Brown M.S. Goldstein J.L. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the sterol content of cells is to metabolic of the the binding of to the and transcription of genes of 7α-hydroxylase in cells that do not normally express the cellular content of mature SREBP1 McArdle rat hepatoma cells express all of the genes to and apoB-containing lipoproteins S. In Cell Biol. PubMed Scopus Google Scholar, J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, J. S. Olofsson J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), 7α-hydroxylase by expressing 7α-hydroxylase in McArdle hepatoma cells, we were to the cellular content of mature SREBP1 to in single cell These cells a opportunity to SREBP1 may of the steps of the VLDL assembly/secretion pathway. The results that SREBP1 coordinately many of the individual and protein used for were Cell was and fetal bovine serum enzymes were New The were the following: hamster MTP was a and C. D.A. Wetterau J.R. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar); hamster HMG-CoA was rat 7α-hydroxylase was a S. D.W. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar); and acetyl-CoA carboxylase was a M.K. S. 1996; PubMed Scopus Google Scholar). A cell was in and the the was R.A. Borchardt R.A. J. Lipid Res. Full Text PDF PubMed Google Scholar). A a was a McArdle hepatoma cells, a were in Dulbecco's modified Eagle's containing fetal bovine and and The cells were in an of with A was in which the of rat 7α-hydroxylase was in a and Stable expression of the in McArdle cells was by and for J. S. Trawick J.D. Davis R.A. S. 1992; PubMed Scopus Google Scholar). cell clones of cells were was cells a of the as J.D. S. Davis R.A. J. Lipid Res. 1996; Full Text PDF PubMed Google Scholar). to of the mRNA was by gel to a and with Cells were in containing a and a and membrane were the by Wang X. Brown M.S. Hua X. Goldstein J.L. 1994; Full Text PDF PubMed Scopus Google Scholar). Cells were for and the were in of cell 1 and The cells were by through a and for The was with an of 1 and and for The was used as for The microsomal membrane was by of the the by for a was as J. Wang Davis R.A. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). the were The binding of the were by of the The relative of to the the membrane was with the were the McArdle and cells were to which the cells were in for the the cells were for with containing in the of 1 cells and were as J. Wang Davis R.A. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), and cells were with and in 1 of and were as J. Wang Davis R.A. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). Cells were in with for with gel and the in free triglycerides, and cholesterol was R.A. Malone-McNeal M. Archambault-Schexnayder J. J. Biol. Chem. 1983; Full Text PDF PubMed Google Scholar). The cellular content of free and cholesterol was in cells to by as (14Dueland S. Trawick J.D. Nenseter M.S. MacPhee A.A. Davis R.A. J. Biol. Chem. 1992; 267: 22695-22698Abstract Full Text PDF PubMed Google Scholar). are as was by and of was by of were to be The of data individual single cell clones used for linear to to of a single cell data were used and were McArdle cells were with a that and a expression of the of rat 7α-hydroxylase. single cell clones were and single cell of McArdle cells expressing 7α-hydroxylase was used for metabolic single cell clones were used to metabolic cell clones of cells expressed 7α-hydroxylase mRNA and protein of the the used and McArdle rat hepatoma cells express all of the gene for VLDL assembly and secretion S. In Cell Biol. PubMed Scopus Google Scholar, J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, J. S. Olofsson J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), show expression of 7α-hydroxylase mRNA protein A cell clones of McArdle cells with were to with to SREBP1, 7α-hydroxylase, and albumin. the of in the cell was as an for and The cellular content of mature SREBP1 was the content of the was decreased in cells expressing 7α-hydroxylase cells and McArdle cells with 25-hydroxycholesterol, an of SREBP1 proteolytic X. Brown M.S. Hua X. Goldstein J.L. 1994; Full Text PDF PubMed Scopus Google Scholar), decreased the content of mature SREBP1 by the was increased of all of the single cell clones showed that the cellular content of mature SREBP1 as a linear of 7α-hydroxylase protein studies show that the cellular content of was not significantly by the expression of 7α-hydroxylase not The secretion of and by McArdle and cells was by of The were by and the of apoB100 by cells was increased by with McArdle cells were in the secretion of by the cell the expression of apoB mRNA was the increased secretion of apoB100 was the result of a of the single cell clones showed that the secretion of apoB100 as a linear of 7α-hydroxylase protein The content of MTP mRNA was significantly increased in cells expressing 7α-hydroxylase as with McArdle Using individual of cells was a in the content of MTP mRNA relative to in cells with McArdle cells the relative of MTP mRNA in to the relative of 7α-hydroxylase mRNA These data that expression of 7α-hydroxylase in McArdle cells the expression of MTP mRNA. with cells, in cells the synthesis of all VLDL lipids (cholesterol, cholesterol esters, triglycerides, and was significantly increased as by the of the cellular content of mature SREBP is to the sterol content of cells (15Briggs M.R. Yokoyama C. Wang X. Brown M.S. Goldstein J.L. J. Biol. Chem. 1993; 268: 14490-14496Abstract Full Text PDF PubMed Google Scholar, 16Wang X. Briggs M.R. Hua X. Yokoyama C. Goldstein J.L. Brown M.S. J. Biol. Chem. 1993; 268: 14497-14504Abstract Full Text PDF PubMed Google Scholar, X. Brown M.S. Hua X. Goldstein J.L. 1994; Full Text PDF PubMed Scopus Google Scholar, J. Hua X. Brown M.S. Goldstein J.L. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), we the cellular content of free and cholesterol in McArdle and cells In cells, expressing 7α-hydroxylase, the cellular content of free and cholesterol was and of the in McArdle cells was and results were that several control sterol and fatty synthesis, are for transcription (15Briggs M.R. Yokoyama C. Wang X. Brown M.S. Goldstein J.L. J. Biol. Chem. 1993; 268: 14490-14496Abstract Full Text PDF PubMed Google M.K. S. 1996; PubMed Scopus Google Scholar, J. Edwards P.A. S. 1996; PubMed Scopus Google Scholar, J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, M.K. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of the mRNA's encoding HMG-CoA reductase, the in cholesterol and acetyl-CoA the in fatty synthesis, was increased in cells with McArdle cells In contrast, the relative of SREBP1 mRNA was in cell the expression of HMG-CoA and acetyl-CoA carboxylase mRNA as a linear relationship with the expression of 7α-hydroxylase mRNA. These data suggest that the expression of genes responsible for the of cholesterol and the fatty in VLDL is coordinately by the expression of 7α-hydroxylase in McArdle the synthesis of and the secretion of apoB100 to the of McArdle hepatoma cells T.L. Boren J. Yamanaka S. Olofsson S.-O. J. Biol. Chem. 1996; 271: 2353-2356Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). induction of synthesis the for secretion of we examined the of the cellular content and secretion of apoB100 in and cells In McArdle and cells, increased the cellular content of apoB100 by and to the increased the secretion of apoB100 by McArdle cells The of apoB100 secretion by McArdle cells was not significantly the secretion of protein not These data of that in McArdle hepatoma cells, apoB100 secretion not secretion J. J. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). increased the secretion of apoB100 by McArdle cells, the secretion of apoB100 by cells expressing 7α-hydroxylase significantly the cellular content of apoB100 in cells, less the in McArdle cells the apoB100 secretion in cells be to apoB100 that cells to as do increased content of cellular apoB change in secretion R.A. Boogaerts J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Clin. Invest. 1983; PubMed Scopus Google Scholar). the that 7α-hydroxylase apoB100 secretion through a McArdle and cells were with and without cholesterol for The proteolytic of SREBP precursors to the mature transcriptionally active is by X. Brown M.S. Hua X. Goldstein J.L. 1994; Full Text PDF PubMed Scopus Google Scholar). to to the cellular content of mature SREBP1 in cells decreased the secretion of apoB100 to that were to of McArdle cells In the of 25-hydroxycholesterol, cells apoB100 McArdle In the of 25-hydroxycholesterol, cell amounts of not significantly the secretion of apoB100 in McArdle cells, decreased the secretion of apoB100 in cells by The secretion of and by of cells was and by was and results were The data suggest that the secretion of apoB100 by McArdle cells expressing 7α-hydroxylase be reversed to in McArdle cells by The that the of mature SREBP1 in cells to of McArdle cells that SREBP1 mediates the secretion of apoB100 caused by expression of 7α-hydroxylase. SREBP was as the transcription that mediates the regulation of LDL receptor gene (15Briggs M.R. Yokoyama C. Wang X. Brown M.S. Goldstein J.L. J. Biol. Chem. 1993; 268: 14490-14496Abstract Full Text PDF PubMed Google Scholar). Its rat was as a transcription in R.A. Biol. 1993; PubMed Scopus Google Scholar), suggesting that may a in regulating the expression of genes in the and of several of studies show that many of the genes encoding enzymes are HMG-CoA X. Brown M.S. Hua X. Goldstein J.L. 1994; Full Text PDF PubMed Scopus Google Scholar), HMG-CoA J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar), J. Edwards P.A. S. 1996; PubMed Scopus Google Scholar), and J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). that the genes for fatty M.K. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar) and acetyl-CoA carboxylase M.K. S. 1996; PubMed Scopus Google Scholar) are SREBP The data derived studies now the metabolic of to a influence several steps of the VLDL assembly/secretion pathway. the expression of 7α-hydroxylase in McArdle hepatoma cells, we were to single cell clones a large in the cellular content of mature SREBP1 that as a linear of 7α-hydroxylase protein content is to that in the cellular content of mature is increased in the of with which the expression of 7α-hydroxylase Brown M.S. Goldstein J.L. S. 1995; PubMed Scopus Google Scholar). The through which 7α-hydroxylase expression the cellular content of mature SREBP1 in is not may the of SREBP cleavage by P.A. Davis R.A. Vance D.E. Vance J. New Comprehensive Biochemistry. Elsevier Science Publishers B.V., Amsterdam1996: Scholar). The data and the that SREBP1 coordinately the assembly and secretion of apoB-containing lipoproteins. 7α-hydroxylase expression is the we to cells, changes in lipoprotein assembly and secretion are the of this liver-specific gene S. D.W. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). These linear between 7α-hydroxylase mRNA and the expression of encoding the enzymes regulating fatty and sterol synthesis carboxylase and HMG-CoA and As a result of the increased expression of these and cells increased synthesis of all lipoprotein lipids (cholesterol, cholesterol esters, triglycerides, and These changes in and MTP expression may be responsible for the increased secretion of as by the linear relationship between the cellular content of 7α-hydroxylase and mature SREBP1 is that the changes in the expression of genes regulating sterol and fatty and the assembly of apoB-containing lipoproteins caused by 7α-hydroxylase expression are through the of the cellular content of mature SREBP1. The findings that 1) expression of 7α-hydroxylase decreased the cellular content of free and cholesterol and 2) concomitantly the cellular content of mature SREBP1 in cells and the secretion of apoB100 to the by McArdle cells that the cellular content of mature SREBP1 is responsible for these this we propose that SREBP1 is a responsible for coordinate regulation of the lipoprotein assembly and secretion pathway in McArdle hepatoma is to that in cell liver in Brown M.S. Goldstein J.L. S. 1995; PubMed Scopus Google may changes in lipoprotein assembly and studies in show that in a hepatoma cell to express liver-specific genes not expressed by McArdle cells, the expression of the MTP and the cell and SREBP1 may to changes in lipoprotein assembly and coordinate regulation a for the of lipids and apoB100 for the liver to is now that secretion of apoB is regulated by a process that the of apoB that the lipoprotein assembly/secretion pathway is in the endoplasmic reticulum (1Davis R.A. Vance J. Vance D.E. Vance J. New Comprehensive Biochemistry. 31. Elsevier Science Publishers B.V., Amsterdam1996: 473-494Google Scholar, 2Innerarity T.L. Boren J. Yamanaka S. Olofsson S.-O. J. Biol. Chem. 1996; 271: 2353-2356Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 9Ginsberg H.N. Curr. Opin. Lipidol. 1995; 6: 275-280Crossref PubMed Scopus (72) Google Scholar). and of showed that the translocation of apoB across the endoplasmic reticulum is R.A. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). consisting of apoB to be the the of apoB that is the be as a lipoprotein particle R.A. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). studies hepatoma cells X. J.L. Ginsberg H.N. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar) and McArdle rat hepatoma cells Vance J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar) showed that the of and the of apoB translocation across the endoplasmic that the of lipids is translocation apoB is to be The of the of apoB in cells J.A. Davis R.A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the of is for translocation and of apoB H.N. Curr. Opin. Lipidol. 1995; 6: 275-280Crossref PubMed Scopus (72) Google Scholar), the and of MTP is In Chinese hamster ovary cells, which do not normally express MTP, all of the apoB a expressed is translocation and by a process J. S. Trawick J.D. Davis R.A. S. 1992; PubMed Scopus Google Scholar, J. Wang Davis R.A. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). In the of MTP the secretion of apoB by hepatoma cells, which do express MTP S. D.A. J. Biol. Chem. 1996; 271: Scholar). Our results that the increased secretion of apoB100 with MTP and mature SREBP1, was not with any change in apoB mRNA suggest that a is The that the secretion of apoB100 by McArdle hepatoma cells, in McArdle cells expressing 7α-hydroxylase the that SREBP1 induction of genes regulating the for lipids in the lipoprotein assembly pathway of Our findings that in cells increased the cellular content of not suggest that the was The of to the secretion of apoB100 in cells that of the processes to and apoB100 lipoproteins is these data is to that in McArdle cells, the of lipids is in of is for lipoprotein MTP for apoB100 translocation and the assembly and secretion of apoB100-containing lipoproteins. Our results may of is not with increased apoB secretion in rat R.A. Boogaerts J.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Clin. Invest. 1983; PubMed Scopus Google Scholar), the secretion of apoB by hepatoma cells J. Lipid Res. Full Text PDF PubMed Google Scholar, J.D. J. J. 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Full Text PDF PubMed Google the secretion of apoB-containing lipoproteins. to propose that a in the of of the for the of apoB and assembly of the lipoprotein particle the pathway. of lipids and apoB for lipoprotein assembly requires that essential protein and component be in relative to the to the lipoprotein changes of the individual processes for VLDL assembly and secretion are invoked in response to state (reviewed in R.A. Vance D. Vance J. of and Elsevier Science Publishers B.V., Scholar). carbohydrate to a coordinate in the synthesis of all lipoprotein lipids and an of all of the processes to the secretion of apoB-containing lipoproteins (10Boogaerts J.R. Malone M.M. Archambault S.J. Davis R.A. Am. J. Physiol. 1984; 246: E77-E83Crossref PubMed Google Scholar). fasting to the decreased apoB increased apoB decreased and decreased lipoprotein secretion (12Davis R.A. Boogaerts J.R. Borchardt R.A. Malone-McNeal M. Archambault-Schexnayder J. J. Biol. Chem. 1985; 260: 14137-14144Abstract Full Text PDF PubMed Google Scholar, 13Leighton J.K. Joyner J. Zamarripa J. Deines M. Davis R.A. J. Lipid Res. 1990; 31: 1663-1668Abstract Full Text PDF PubMed Google Scholar). development a change in apoB and lipoprotein secretion (11Coleman R.A. Haynes E.B. Sand T.M. Davis R.A. J. Lipid Res. 1988; 29: 33-42Abstract Full Text PDF PubMed Google Scholar). These findings led us to propose that metabolic signals is responsible for the coordinate regulation of and the of Our data show that expression of 7α-hydroxylase in McArdle cells the cellular content of mature SREBP1 in a that coordinately changes the of lipids and the processes to apoB-containing lipoproteins. that in McArdle cells expressing 7α-hydroxylase, the cellular content of mature SREBP1 and the secretion of Our findings may the that in with known to the expression of 7α-hydroxylase, is a in the secretion of VLDL J. Lipid Res. Full Text PDF PubMed Google Scholar, and J. Clin. Scholar). in to be a between the of synthesis, a linked to 7α-hydroxylase and secretion J. Lipid Res. Full Text PDF PubMed Google Scholar, and J. Clin. Scholar). The data suggest that changes in cholesterol may alter VLDL assembly and secretion by 1) the of cholesterol and cholesterol that are for VLDL assembly and 2) by the cellular content of mature is through the content of mature that coordinate response of the gene the of lipids and and MTP is linked to the production of VLDL in may require coordinate induction of all of the gene for the synthesis of individual lipids and for assembly with apoB may be to in which VLDL secretion by the liver is by a coordinate regulation of gene expression by M. J. PubMed Scopus Google Scholar, A.M. Biol. 31: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.A. J. Scholar). is to that VLDL production may not be all in may which of the many processes are for VLDL assembly the provided for these to SREBP1 and for acetyl-CoA Briggs to for rat 7α-hydroxylase used for expression Lusis for the for rat apoB, and and for the MTP and Trawick for in the expressing 7α-hydroxylase. In we for of the and