A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression

It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3′UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation. It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3′UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation. The expression of liver LDL receptor (LDLR) regulates human plasma LDL-cholesterol (LDL-C) homeostasis (1Spady D.K. Hepatic clearance of plasma low density lipoproteins.Semin. Liver Dis. 1992; 12: 373-385Crossref PubMed Scopus (41) Google Scholar, 2Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Scopus (4586) Google Scholar, 3Goldstein J.L. Brown M.S. Regulation of the mevalonate pathway.Nature. 1990; 343: 425-430Crossref PubMed Scopus (4794) Google Scholar). 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Blunted feedback suppression of SREBP processing by dietary cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N).J. Clin. Invest. 1998; 102: 2050-2060Crossref PubMed Scopus (58) Google Scholar), it is currently unknown whether elevated cholesterol levels can also elicit a cellular response to increase LDLR mRNA turnover rate as a rapid means to lower LDLR expression and to further reduce cholesterol uptake from outside of cells. The stability of LDLR mRNA is modulated through its 3′ untranslated region (UTR) (16Yamamoto T. Davis C.G. Brown M.S. Schneider W.J. Casey M.L. Goldstein J.L. Russell D.W. The human LDL receptor: A cysteine-rich protein with multiple Alu sequence in its mRNA.Cell. 1984; 39: 27-38Abstract Full Text PDF PubMed Scopus (1064) Google Scholar). This region harbors four adenylate-uridylate (AU)-rich elements (AREs) (8Wilson G.M. Vasa M.Z. Deeley R.G. Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3′ untranslated region.J. Lipid Res. 1998; 39: 1025-1032Abstract Full Text Full Text PDF PubMed Google Scholar, 9Wilson G.M. Roberts E.A. Deeley R.G. Modulation of LDL receptor mRNA stability by phorbol esters in human liver cell culture models.J. Lipid Res. 1997; 38: 437-446Abstract Full Text PDF PubMed Google Scholar, 17Yashiro T. Yokoi Y. Shimizu M. Inoue J. Sato R. Chenodeoxycholic acid stabilization of LDL receptor mRNA depends on 3′-untranslated region and AU-rich element-binding protein.Biochem. Biophys. Res. Commun. 2011; 409: 155-159Crossref PubMed Scopus (13) Google Scholar) that are docking sites for cytoplasmic ARE-binding proteins (ARE-BPs). Some ARE-BPs are mRNA destabilizing inducers, while others can protect the mRNA from endonuclease cleavage (18Barreau C. Paillard L. Osborne H.S. 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Identification of mRNA-binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements.J. Lipid Res. 2009; 50: 820-831Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). A recent new study identified human antigen R (HuR) as a stabilizing factor for LDLR mRNA T. M. Shimizu M. Inoue J. Sato R. low density receptor mRNA in via binding to AU-rich Full Text Full Text PDF PubMed Scopus (26) Google Scholar). It in HepG2 cells that bound to the ARE site of LDLR 3′UTR and to increase in LDLR mRNA In addition to LDLR ARE-BPs have been to regulate the stability of other mRNA with cellular and cell S. Wang W. G.M. G. M. of expression by is mediated by mRNA Biol. PubMed Scopus Google Scholar, S. Schneider mRNA decay factor and suppression of by of Full Text Full Text PDF PubMed Scopus Google Scholar, P. Chen M. M. M. A. R. many for a 2011; PubMed Scopus Google Scholar, T. M. M. G. Chen L. P. R. Identification of a of target transcripts by Mol. Biol. PubMed Scopus Google Scholar, I. D. C. of and in mRNA turnover by RNA Acids Res. 2004; PubMed Scopus Google Scholar). there is the effect of on the expression activity of LDLR mRNA binding In this current study, we the dietary cholesterol and LDLR mRNA binding proteins to a regulatory role of dietary cholesterol on LDLR mRNA we examined the expression of LDLR ARE-BPs in liver of mice and a diet a high cholesterol diet that the hepatic expression of LDLR mRNA decay promoting factor HNRNPD specifically by in mice as as in while expressions of HNRNPI, and by high cholesterol This in vivo in in studies of hepatic cell the of elevated HNRNPD levels on LDL-C we the approach of adenovirus-mediated gene Our results demonstrated that HNRNPD-mediated degradation of LDLR mRNA on of liver LDLR and reduction of serum LDL-C hypercholesterolemic This work the evidence that dietary cholesterol inhibits LDLR gene expression through the of transcriptional suppression and of mRNA from and from transgenic mice and in the of Li H. Liu J. The role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein in 3′ untranslated decay of receptor mRNA in liver Thromb. Vasc. Biol. PubMed Scopus Google Scholar). to mice and in the diet and to and diet mice and a a cholesterol for 2 mice a a for for and for serum and liver and at for RNA and protein animal and and by the and of the In study, mice a for 2 mice with with mice with and mice with a control at a of via in a of of serum 2 to and at and the and and at for of RNA and protein In study, mice with serum lipid levels with at a of via in a of of and the of mice for for serum and liver with the In as Li H. Liu J. The role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein in 3′ untranslated decay of receptor mRNA in liver Thromb. Vasc. Biol. PubMed Scopus Google Scholar). mice of and with from mice as by and for a region of and The 1 to the the from mice a mice with mice in with of mice in the other with of as the control via in a of of and the of of the animals. as the for of protein and activity at and at to cholesterol and with from RNA from liver of and as Liu J. diet expression in liver of via Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). liver in sequences of genes in are in I. mRNA expression in to the The to mRNA expression of liver from mice in 1 and protein of proteins for and hepatic cells, of cell proteins for and HNRNPD with from and by from LDLR from receptor from with of and with the with by of of hepatoma HepG2 cells and hepatoma cells from HepG2 cells cultured in with cells cultured in a of and with cholesterol cells in culture and cultured in serum The cells with cholesterol cholesterol and 1 of other for of RNA and cell In for Liver of mice in cell culture of liver protein activity from liver and to The in serum of mice a from to the are as with mice a for serum cholesterol levels by from to and serum LDL-C by from to as with mice a whether a hepatic expressions of LDLR mRNA binding we examined mRNA levels of HNRNPI, and in liver of mice and to mice. that a HNRNPD mRNA levels by without affecting HNRNPI, mRNA In and as mRNA levels of LDLR and other target and decreased by feeding HNRNPD protein has four and by mRNA splicing G. The role of in mRNA Google Scholar, P. Chen a cytoplasmic role for in the in vivo mRNA by the AU-rich 1999; PubMed Scopus Google Scholar, A. for RNA binding by and Biochem. PubMed Scopus Google Scholar). In liver and primary the and Li H. Liu J. The role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein in 3′ untranslated decay of receptor mRNA in liver Thromb. Vasc. Biol. PubMed Scopus Google Scholar). we examined and LDLR protein levels in liver of the and The results demonstrated that feeding both HNRNPD and to and of control and reduced LDLR protein abundance to of control with the gene expression protein levels of diet we whether the elevated expression of HNRNPD feeding in other animal this we a a for 2 and examined HNRNPD mRNA and protein expressions in liver The serum in a as with a A the HNRNPD mRNA level and reduced the LDLR mRNA level by as with a further the of HNRNPD protein expression in hamster liver by feeding The in hamster in the diet study, we in mRNA protein levels of in hamster feeding Altogether, results for the that to a diet by HNRNPD expression in liver LDLR expressions In previous in we to a that of and human of in primary to reduce HNRNPD mRNA and protein levels without affecting mRNA levels of other ARE-BPs genes Li H. Liu J. The role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein in 3′ untranslated decay of receptor mRNA in liver Thromb. Vasc. Biol. PubMed Scopus Google Scholar). it is a to the in vivo role of HNRNPD in suppression of liver LDLR control mice that a for 2 the serum lipid levels and of While on a serum cholesterol levels the in control mice a in serum level of in mice with control and serum further to a level which lower control mice of The reduction in serum LDL-C levels by in mice with and as with control mice levels by HNRNPD depletion the we mRNA levels of HNRNPD and LDLR in liver to and mRNA In we mRNA levels of a target and that in mRNA levels of and both reduced to of that in control mice which associated with a marked increase in the LDLR mRNA level to of control In to depletion mRNA levels of other target genes that of liver further demonstrated that the protein level in mice reduced to of control and protein to of control by the expression of HNRNPD This reduction of HNRNPD protein abundance associated with increase of of control in the hepatic LDLR protein level of and the associated with the of as a factor for reduced serum cholesterol In we serum we knockdown of HNRNPD expression in liver on serum results the in vivo evidence a key role of HNRNPD in of hepatic LDLR expression hypercholesterolemic we examined the effect of in normolipidemic mice. at the mice a in a decrease in and LDL-C with the control mice with levels by of hepatic gene expression by that the substantial of HNRNPD in mice LDLR mRNA levels to of control In addition to LDLR and we mRNA levels of other LDLR ARE-BPs and and genes in the cholesterol pathway and in liver The results that of mRNA levels by further demonstrated that LDLR protein levels to of control by while HNRNPD and reduced to and of control in normolipidemic demonstrated that hepatic depletion of HNRNPD a on LDLR expression and on of serum cholesterol normolipidemic In we mRNA and protein levels of HNRNPD in liver of control mice a we in HNRNPD mRNA and protein levels in mice. we further mRNA levels of HNRNPD G. The role of in mRNA Google Scholar) and in liver with HNRNPD expression by mRNA levels of four of HNRNPD transcripts reduced in liver of mice with mice. by we liver LDLR protein levels in four of control mice a and mice both that a cholesterol diet LDLR by as with the in mice. of HNRNPD in a increase in and a increase in as with LDLR protein levels in control mice a the increase in LDLR abundance by HNRNPD depletion when with control that in this depletion of HNRNPD can dietary of hepatic the results of protein and mRNA from and mice demonstrate that cholesterol feeding elevates the LDLR mRNA protein and that HNRNPD in liver in LDLR mRNA and protein which a substantially improved of serum LDL-C in hypercholesterolemic mice. further the mechanism of increase in hepatic LDLR we transgenic mice that gene the control of promoter Li H. Liu J. The role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein in 3′ untranslated decay of receptor mRNA in liver Thromb. Vasc. Biol. PubMed Scopus Google Scholar). is a unique in vivo to study the of 3′UTR in LDLR mRNA decay in liver tissue. mice with with a control while mice on a and of on mice. of of and mice. is the results that the control further vivo activity of liver and a activity in as with control we liver mRNA levels of HNRNPD and LDLR mRNA to expression of HNRNPD in the liver of mice in marked of and mRNA levels with of mRNA level of and LDLR mRNA level of in hepatic mRNA levels of other mRNA binding proteins by In to the inducing effect of cholesterol on HNRNPD expression in HepG2 cells and cells cultured in and with cholesterol for expression by that cholesterol HNRNPD mRNA levels to of control in HepG2 cells and elevated HNRNPD mRNA levels to of control in cells while effect on HNRNPD expression in both cell In to LDLR mRNA levels by cholesterol and strongly elevated by that HNRNPD gene expression is by the SREBP pathway a target of the liver receptor pathway that regulates many genes in cholesterol metabolism in liver D. I. D. et of lipid metabolism and Full Text Full Text PDF PubMed Scopus Google Scholar). It is well-known that and are T. E. Liver receptor and new and Sci. 33: Full Text Full Text PDF PubMed Scopus Google Scholar). of by regulates target genes and inhibits SREBP we HepG2 cells cultured in with and for In this of we and cholesterol as that mRNA levels of of the LDLR and elevated in cells with and HNRNPD mRNA levels by at both and and elevated control by we mRNA levels of target and strongly by to the in HepG2 cells, we substantial in HNRNPD mRNA levels in cells with in and mRNA levels Altogether, results show that in cultured hepatic cells, HNRNPD mRNA expression and elevated by it to of The by which cholesterol HNRNPD expression to It has been well-established that cholesterol feeding reduces LDLR mRNA and multiple in the cholesterol pathway in the of mice B.S. Shimomura I. Bashmakov Y. Hammer R.E. Horton J.D. Goldstein J.L. Brown M.S. Blunted feedback suppression of SREBP processing by dietary cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N).J. Clin. Invest. 1998; 102: 2050-2060Crossref PubMed Scopus (58) Google Scholar) and (13Sheng Z. Otani H. Brown M.S. Goldenstein J.L. Independent regulation of sterol regulatory element-binding pro­teins 1 and 2 in hamster liver.Proc. Natl. Acad. Sci. USA. 1995; 92: 935-938Crossref PubMed Scopus (288) Google Scholar, I. Bashmakov Y. Shimano H. Horton J.D. Goldstein J.L. Brown M.S. Cholesterol feeding reduces nuclear forms of sterol regulatory element binding proteins in hamster liver.Proc. Natl. Acad. Sci. USA. 1997; 94: 12354-12359Crossref PubMed Scopus (127) Google Scholar). of dietary cholesterol in the liver the proteolytic of and to a in the expression of SREBP target LDLR and it has been that this transcriptional suppression is the mechanism for reduced LDLR mRNA The results from this current study for the that dietary cholesterol reduces liver LDLR mRNA through of transcriptional suppression and of mRNA decay mediated by the LDLR mRNA decay promoting ARE binding this study by the cholesterol feeding and cellular abundance of LDLR mRNA binding previous in along with other LDLR ARE-BPs and demonstrated to as mRNA decay-promoting factors (21Li H. Chen W. Zhou Y. Abidi P. Sharpe O. Robinson W.H. Liu J. Identification of mRNA-binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements.J. Lipid Res. 2009; 50: 820-831Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). of proteins in HepG2 cells in of LDLR negative a recent study that a ARE binding of binding the ARE site of LDLR mRNA 3′UTR and the mRNA T. M. Shimizu M. Inoue J. Sato R. low density receptor mRNA in via binding to AU-rich Full Text Full Text PDF PubMed Scopus (26) Google Scholar). we examined the mRNA expression of negative and of LDLR mRNA stability in of a diet dietary cholesterol a to that feeding a specifically and elevated the expression of HNRNPD in liver tissue. The of HNRNPD mRNA and protein by a in both mice and that this mRNA decay-promoting protein to the of LDLR mRNA levels in a that of and human Our previous in studies have demonstrated that of in primary as as in HepG2 cells, substantially reduced HNRNPD cellular levels with in LDLR mRNA and protein levels Li H. Liu J. The role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein in 3′ untranslated decay of receptor mRNA in liver Thromb. Vasc. Biol. PubMed Scopus Google Scholar). in the study with this in we to whether knockdown of this decay-promoting protein increase liver LDLR expression and serum LDL-C and in in LDLR mRNA stability the on serum LDL-C of control to mice a a Our results that with normolipidemic reduction of hepatic HNRNPD protein in hyperlipidemic mice on of liver LDLR mRNA levels in mice in and on serum and LDL-C new that when the intracellular cholesterol level is elevated due to and the SREBP pathway is stabilizing LDLR mRNA by HNRNPD-mediated mRNA decay a means to increase hepatic LDLR activity to LDL-C from the This The of HNRNPD in mRNA turnover has been studies that HNRNPD-mediated mRNA decay in a cell culture P. Chen a cytoplasmic role for in the in vivo mRNA by the AU-rich 1999; PubMed Scopus Google Scholar, A. for RNA binding by and Biochem. PubMed Scopus Google Scholar) a cell K. Kuwano Y. M. J.L. A. M. Identification of a in target of protein Acids Res. 2009; PubMed Scopus Google Scholar, G.M. of ribonucleoprotein by AU-rich element protein 1 and RNA Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). results the strong of HNRNPD cellular abundance with LDLR mRNA levels in it to demonstrate that the effect of HNRNPD mediated through without the of LDLR gene transcription in Our transgenic is the in vivo to study the of 3′UTR in liver in mice. by the the is in liver tissue. the transgenic mice with the control we that adenovirus-mediated depletion of HNRNPD strongly hepatic and mRNA expression along with LDLR mRNA levels in transgenic mice. in vivo the mechanism of via HNRNPD-mediated LDLR mRNA degradation through In this study, we to the cholesterol of HNRNPD in cultured hepatoma cells of and of HNRNPD mRNA levels in hepatic cell the as with in vivo have also hepatic cells with that are strong of to of HNRNPD mRNA expression in cultured hepatic cells. dietary cholesterol HNRNPD expression in liver and further in are to the HNRNPD has been to regulate the stability translational of mRNA G. The role of in mRNA Google Scholar). of its target proteins in the cell In the studies of HNRNPD have been on its target and is HNRNPD is in disease The results of current studies demonstrate the key role of HNRNPD in regulation of lipid metabolism by also its regulation by dietary cholesterol in liver tissue. While the the inducing effect of cholesterol feeding on hepatic HNRNPD expression in mice and further results from the current study to a in which of intracellular in liver reduce LDLR mRNA and protein on the of by the binding of to of the LDLR promoter and by the of HNRNPD with ARE of the This unique regulation at the transcriptional and posttranscriptional levels a response of liver to to reduce cholesterol uptake from in to cellular cholesterol with element element-binding protein adenylate-uridylate high cholesterol diet heterogeneous nuclear ribonucleoprotein human antigen R KH-type splicing regulatory protein LDL-cholesterol LDL receptor serum receptor 3′ untranslated region liver receptor diet sterol-regulatory element sterol-regulatory element binding protein receptor untranslated region