Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells

Metabolic disorders such as type 2 diabetes cause hepatic endoplasmic reticulum (ER) stress, which affects neutral lipid metabolism. However, the role of ER stress in cholesterol metabolism is incompletely understood. Here, we show that induction of acute ER stress in human hepatic HepG2 cells reduced ABCA1 expression and caused ABCA1 redistribution to tubular perinuclear compartments. Consequently, cholesterol efflux to apoA-I, a key step in nascent HDL formation, was diminished by 80%. Besides ABCA1, endogenous apoA-I expression was reduced upon ER stress induction, which contributed to reduced cholesterol efflux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol efflux, cellular cholesterol levels remained unchanged during ER stress. This was due to impaired de novo cholesterol synthesis by reduction of HMG-CoA reductase activity by 70%, although sterol response element-binding protein-2 activity was induced. In mice, ER stress induction led to a marked reduction of hepatic ABCA1 expression. However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress. Taken together, our data suggest that ER stress in metabolic disorders reduces HDL biogenesis due to impaired hepatic ABCA1 function. Metabolic disorders such as type 2 diabetes cause hepatic endoplasmic reticulum (ER) stress, which affects neutral lipid metabolism. However, the role of ER stress in cholesterol metabolism is incompletely understood. Here, we show that induction of acute ER stress in human hepatic HepG2 cells reduced ABCA1 expression and caused ABCA1 redistribution to tubular perinuclear compartments. Consequently, cholesterol efflux to apoA-I, a key step in nascent HDL formation, was diminished by 80%. Besides ABCA1, endogenous apoA-I expression was reduced upon ER stress induction, which contributed to reduced cholesterol efflux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol efflux, cellular cholesterol levels remained unchanged during ER stress. This was due to impaired de novo cholesterol synthesis by reduction of HMG-CoA reductase activity by 70%, although sterol response element-binding protein-2 activity was induced. In mice, ER stress induction led to a marked reduction of hepatic ABCA1 expression. However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress. Taken together, our data suggest that ER stress in metabolic disorders reduces HDL biogenesis due to impaired hepatic ABCA1 function. HDL removes excess cholesterol from macrophage foam cells in atherosclerotic plaques and is therefore considered to protect from cardiovascular diseases (1.Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.N. Engl. J. Med. 2007; 357: 1301-1310Crossref PubMed Scopus (1295) Google Scholar). ApoA-I, the main apolipoprotein of HDL, is secreted by liver and intestine and acquires phospholipids and cholesterol upon interaction with ABCA1 to form nascent, discoid HDL (2.Duong P.T. Collins H.L. Nickel M. Lund-Katz S. Rothblat G.H. Phillips M.C. Characterization of nascent HDL particles and microparticles formed by ABCA1-mediated efflux of cellular lipids to apoA-I.J. Lipid Res. 2006; 47: 832-843Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 3.Sorci-Thomas M.G. Owen J.S. Fulp B. Bhat S. Zhu X. Parks J.S. Shah D. Jerome W.G. Gerelus M. Zabalawi M. et al.Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers.J. Lipid Res. 2012; 53: 1890-1909Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 4.Kang M.H. Singaraja R. Hayden M.R. Adenosine-triphosphate-binding cassette transporter-1 trafficking and function.Trends Cardiovasc. Med. 2010; 20: 41-49Crossref PubMed Scopus (41) Google Scholar, 5.Brunham L.R. Kruit J.K. Iqbal J. Fievet C. Timmins J.M. Pape T.D. Coburn B.A. Bissada N. Staels B. Groen A.K. et al.Intestinal ABCA1 directly contributes to HDL biogenesis in vivo.J. Clin. Invest. 2006; 116: 1052-1062Crossref PubMed Scopus (419) Google Scholar). The importance of ABCA1 in this process is well established: In mice lacking hepatic ABCA1, reduced HDL levels and increased macrophage foam cell formation are observed (6.McNeish J. Aiello R.J. Guyot D. Turi T. Gabel C. Aldinger C. Hoppe K.L. Roach M.L. Royer L.J. de Wet J. et al.High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.Proc. Natl. Acad. Sci. USA. 2000; 97: 4245-4250Crossref PubMed Scopus (481) Google Scholar). In Tangier disease, lack of functional ABCA1 causes severe HDL deficiency (7.Rust S. Rosier M. Funke H. Real J. Amoura Z. Piette J.C. Deleuze J.F. Brewer H.B. Duverger N. Denefle P. et al.Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.Nat. Genet. 1999; 22: 352-355Crossref PubMed Scopus (1264) Google Scholar). Moreover, patients with loss of function mutations in ABCA1 display an increased atherosclerotic burden (8.Bochem A.E. van Wijk D.F. Holleboom A.G. Duivenvoorden R. Motazacker M.M. Dallinga-Thie G.M. de Groot E. Kastelein J.J. Nederveen A.J. Hovingh G.K. et al.ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.Eur. Heart J. 2013; 34: 286-291Crossref PubMed Scopus (58) Google Scholar). Adipose tissue ABCA1 contributes to systemic HDL biogenesis (9.Chung S. Sawyer J.K. Gebre A.K. Maeda N. Parks J.S. Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo.Circulation. 2011; 124: 1663-1672Crossref PubMed Scopus (72) Google Scholar). In contrast, ABCG1 and scavenger receptor class B, type I (SR-BI) are not found to be necessary for nascent HDL formation in murine primary hepatocytes (10.Ji A. Wroblewski J.M. Cai L. de Beer M.C. Webb N.R. van der Westhuyzen D.R. Nascent HDL formation in hepatocytes and role of ABCA1, ABCG1, and SR-BI.J. Lipid Res. 2012; 53: 446-455Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Perturbations of endoplasmic reticulum (ER) homeostasis, referred to as “ER stress”, contribute to metabolic dysregulation (11.Ozcan L. Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders.Annu. Rev. Med. 2012; 63: 317-328Crossref PubMed Scopus (335) Google Scholar, 12.Fu S. Watkins S.M. Hotamisligil G.S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling.Cell Metab. 2012; 15: 623-634Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar). ER stress is sensed by the unfolded protein response (UPR), a collection of conserved signaling pathways that lead to the adaption of the ER (13.Walter P. Ron D. The unfolded protein response: from stress pathway to homeostatic regulation.Science. 2011; 334: 1081-1086Crossref PubMed Scopus (3878) Google Scholar, 14.Scull C.M. Tabas I. Mechanisms of ER stress-induced apoptosis in atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2011; 31: 2792-2797Crossref PubMed Scopus (160) Google Scholar, 15.Colgan S.M. Hashimi A.A. Austin R.C. Endoplasmic reticulum stress and lipid dysregulation.Expert Rev. Mol. Med. 2011; 13: e4Crossref PubMed Scopus (67) Google Scholar). In eukaryotic cells, three ER resident proteins are known to sense ER stress: activating transcription factor 6 (ATF6), protein kinase RNA-like ER kinase (PERK), and inositol requiring protein 1 (IRE1) (13.Walter P. Ron D. The unfolded protein response: from stress pathway to homeostatic regulation.Science. 2011; 334: 1081-1086Crossref PubMed Scopus (3878) Google Scholar). Under normal conditions, glucose-regulated protein 78 (GRP78) binds to the luminal domain of IRE1, ATF6, and PERK to repress the UPR. After ER stress, GRP78 dissociates and causes activation of UPR signaling (15.Colgan S.M. Hashimi A.A. Austin R.C. Endoplasmic reticulum stress and lipid dysregulation.Expert Rev. Mol. Med. 2011; 13: e4Crossref PubMed Scopus (67) Google Scholar). A role for ER stress in lipid metabolism is implied by the fact that the activation processes for ATF6 and sterol response element-binding proteins (SREBPs) are similar (16.Haze K. Yoshida H. Yanagi H. Yura T. Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.Mol. Biol. Cell. 1999; 10: 3787-3799Crossref PubMed Scopus (1537) Google Scholar, 17.Brown M.S. Goldstein J.L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood.Proc. Natl. Acad. Sci. USA. 1999; 96: 11041-11048Crossref PubMed Scopus (1103) Google Scholar). Indeed, ER stress activates SREBPs. For instance, ER stress induction by homocysteine activated in hepatic cells and cells S. J. Austin R.C. endoplasmic reticulum stress and to in gene expression in human 1999; PubMed Google Scholar, S.M. D. G.H. Austin R.C. Endoplasmic reticulum stress causes the activation of sterol binding J. Biol. 2007; PubMed Scopus Google Scholar). ER stress is to a role in in and in human patients H.L. H. I. S. C. T. P. GRP78 expression and ER stress-induced activation and reduces hepatic in Clin. Invest. PubMed Scopus Google Scholar, L. C. N. The of endoplasmic reticulum stress to liver 2011; 53: PubMed Scopus Google Scholar, J. Iqbal J. R. H. J. et pathways to hepatic caused by ER of Cell. 15: Full Text Full Text PDF PubMed Scopus Google Scholar, K. S. J. L. H. R. et unfolded protein response ER stress-induced hepatic J. 2011; PubMed Scopus Google Scholar). lead to hepatic ER stress D. endoplasmic reticulum stress and apoptosis are by in liver Cell. 2007; PubMed Scopus Google and a that lack of from ER stress in the liver T. P. T. H. E. J. D. et of from hepatic endoplasmic reticulum stress in 2012; PubMed Scopus Google Scholar). This was to in hepatic the role of ER stress in during is under I. The role of endoplasmic reticulum stress in the of Res. 2010; PubMed Scopus Google Scholar, G.S. Endoplasmic reticulum stress and Med. 2010; PubMed Scopus Google Scholar, B. C.M. D. M. et endoplasmic reticulum is the of in Biol. PubMed Scopus Google Scholar, J. A.E. S. M. D. M. M. C. Endoplasmic reticulum stress controls macrophage and foam cell Biol. 2012; Full Text Full Text PDF PubMed Scopus Google the role of ER stress in hepatic cholesterol metabolism is that accumulation of hepatic ER cholesterol ER stress and the of L. L. H. L. M. C. L. J. et deficiency hepatic endoplasmic reticulum stress in Biol. 2012; Full Text Full Text PDF Scopus Google Scholar). ER stress is with metabolic in type 2 diabetes and A.K. M. The role for endoplasmic reticulum stress in diabetes Rev. PubMed Scopus Google Scholar). disorders are characterized by and low HDL apoA-I transcription and increased HDL for the reduction in HDL levels P. B.A. The role of HDL in Rev. 2012; PubMed Scopus Google Scholar, L. E. P. B. lipoprotein apolipoprotein in in J. Metab. PubMed Scopus Google Scholar, of apolipoprotein gene expression in 53: PubMed Scopus Google Scholar). In this we the of of cholesterol metabolism in hepatic cells by ER stress HDL metabolism. 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S. M. C. M. H. D. E. et of in the human ATP-binding cassette transporter A1 role of binding and an Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The three sterol M. H. N. T. T. H. K. et of and to of and Lipid Res. Full Text Full Text PDF PubMed Google was by for A for under of a as a were in and 1 with 1 and to the were with and activity was the ABCA1 activity was to was to directly the cellular content of cholesterol and a A. P. L. M. 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HepG2 cells were with for in of to with cholesterol and expression of UPR increased and expression activation of the PERK expression of the ER GRP78 and an ER stress induction by ABCA1 was reduced by a reduction a of ABCA1 was by a reduction of ABCA1 protein expression After ABCA1 expression an expression with expression was observed ABCA1 expression with the reduction expression adaption to ER stress, ABCA1 expression levels ABCA1 is for we by Indeed, redistribution of ABCA1 to tubular perinuclear an to ER stress, HepG2 cells were with reduced ABCA1 and protein expression of and was increased induction of ER stress by in human hepatic cells and human hepatocytes and in murine hepatic cells reduced ABCA1 expression similar to our in HepG2 cells data suggest a role for ER stress in ABCA1 in hepatic cells, of the cell the of ER stress the functional of impaired ABCA1 expression and by ER stress, we cholesterol efflux to reduced cholesterol efflux cholesterol efflux was by a liver X receptor In contrast, cholesterol efflux to HDL was not However, cholesterol efflux was impaired were in The that ER stress cholesterol efflux to the of apoA-I be by the of for ABCA1 in the apoA-I by the reduced efflux to synthesized and secreted Indeed, reduced apoA-I and endogenous apoA-I protein expression data that ER stress reduces the expression of ABCA1 and apoA-I to cholesterol stress apoA-I expression. 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ABCA1 we ABCA1 activity in and binding ER stress reduced ABCA1 activity to of the of a functional binding a ABCA1 activity in the Taken together, data suggest that ER stress ABCA1 expression by a of impaired cholesterol efflux the cellular and cholesterol by that cholesterol content was HepG2 cells were with in the of However, cholesterol was to perinuclear cellular as by show that ER stress cholesterol efflux accumulation of cellular Consequently, we ER stress cholesterol the of ER stress cholesterol we the of and that the cholesterol synthesis in cells in response to the of cholesterol due to This was in cells In the synthesis of cholesterol was However, formation of cholesterol was low and not contribute to cholesterol the activity of HMG-CoA the in the cholesterol HMG-CoA reductase activity was to by ER stress This was HMG-CoA reductase activity was increased as a to This downregulation of cholesterol synthesis by ER stress is in with the that the cellular cholesterol content is impaired cholesterol efflux. that ER stress ER stress induction by in a of the and HMG-CoA reductase Moreover, we activity of the binding activity increased as cells were from to This was was ER stress activity as by gene expression and activity our data that ER stress cholesterol synthesis for HMG-CoA reductase to our key in hepatic cells in which is to ER stress in expression of and in the hepatic ER stress In ABCA1 and apoA-I protein expression levels were reduced which the in Moreover, expression was cholesterol was in mice with with controls However, this was due to reduced cholesterol content in the HDL cholesterol was Taken together, our in and in data that hepatic ER stress ABCA1 expression. In this we for hepatic ER stress and cholesterol metabolism. show that acute ER stress cholesterol efflux and synthesis in hepatic of ER stress in HepG2 cells was by which luminal as well as which protein ABCA1 expression in a 1 and In apoA-I expression was reduced The reduction of ABCA1 and apoA-I in reduced cholesterol efflux were in mice ER stress was by ER stress in was with reduced ABCA1 and apoA-I expression we that hepatic ER stress HDL However, ER stress induction in mice not HDL reduced HDL biogenesis impaired ABCA1 expression is by reduced HDL cholesterol due to reduced expression ABCA1 in hepatic cells is incompletely understood. In peripheral cells, sterol activation of which ABCA1 expression and cholesterol efflux. In contrast, repress ABCA1 transcription in cells N. T. K. K. R. T. T. element-binding and liver X of hepatic transporter A1 gene the response to cellular cholesterol Biol. 2007; Full Text Full Text PDF PubMed Scopus Google and cholesterol not ABCA1 expression in liver cells M. R. J.K. M. of involved in cholesterol metabolism in liver and Full Text Full Text PDF PubMed Scopus Google Scholar). ABCA1 expression is not reduced in mice J. M. D.R. Liver expression is for cholesterol homeostasis and cholesterol in Clin. Invest. 2012; PubMed Scopus Google together, suggest a role of cholesterol and hepatic In with our data show of ABCA1 during ER stress because an ABCA1 lacking an was the of ABCA1 downregulation during ER stress to be In to a ABCA1 expression be by a by ER stress. Indeed, 1 reduced ABCA1 expression by ABCA1 protein expression was reduced by Moreover, ER stress induction in mice reduced ABCA1 protein expression of ABCA1 not which ER stress, reduced ABCA1 protein expression ABCA1 transcription in M. ER stress is with reduced protein levels in with by a J. Biol. 2012; PubMed Scopus Google Scholar). factor of hepatic ABCA1 is which to reduced ABCA1 expression A. S. M.L. N. C. contributes to the of cholesterol 2010; PubMed Scopus Google Scholar). we expression ER stress expression was by in HepG2 cells not Moreover, our data show a reduction in the activity of from the of ABCA1 the of ABCA1 A. S. M.L. N. C. contributes to the of cholesterol 2010; PubMed Scopus Google Scholar). This that not a role in the of ABCA1 under ER stress. ER stress is because is for instance, of of lipids X. P. K. C. S. of and lipids causes acute endoplasmic reticulum stress in 2011; PubMed Scopus Google Scholar). However, ER stress, ER homeostasis be is of to the of metabolic disorders S. Watkins S.M. Hotamisligil G.S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling.Cell Metab. 2012; 15: 623-634Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar). ER stress with reduced ABCA1 The of found reduced ABCA1 expression in the liver and in of mice T. Z. C. S. X. C. C. J. S. et and the expression of the ATP-binding cassette transporter PubMed Scopus Google Scholar). In in and as of ABCA1 expression in HepG2 and the of our we that ER stress is involved in the observed downregulation of ABCA1 in HepG2 cells and ABCA1 expression is reduced in and from patients with diabetes C. D. V. C. J. 2 diabetes is with reduced ATP-binding cassette transporter A1 gene protein and 2011; PubMed Scopus Google Scholar). In ABCA1 protein and function were with ER downregulation of ABCA1 data reduced apoA-I expression upon ER stress are in with of and E. Endoplasmic reticulum stress in HepG2 cells apolipoprotein Sci. 2013; PubMed Scopus Google found reduced apoA-I protein expression and HepG2 cells with and However, the in apoA-I apoA-I In contrast, our data reduced apoA-I upon ER stress and In to reduced cholesterol efflux, we observed reduced cholesterol synthesis ER stress induction, although activity was and This to cellular cholesterol levels in of impaired cholesterol in the of cholesterol our is the to directly show impaired cholesterol synthesis by ER stress, the ER stress and activation the of In mice, is activated of cholesterol, an that was to increased ER stress in deficiency causes a because of hepatic dysregulation with endoplasmic reticulum Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). activation by ER stress was in and cells and in the liver of mice G.H. S. G.S. J. Maeda N. M.R. et endoplasmic reticulum stress causes dysregulation of the cholesterol and Clin. Invest. PubMed Scopus Google Scholar, S.M. D. G.H. Austin R.C. Endoplasmic reticulum stress causes the activation of sterol binding J. Biol. 2007; PubMed Scopus Google Scholar). cellular accumulation of not directly cholesterol and increased cholesterol was due to increased LDL In our we in the of cholesterol and directly cholesterol synthesis by ER stress. In to the and our ER stress induction by ATF6 activity and lipid accumulation in HepG2 cells L. M. Mori K. S. Zhu ATF6 J. PubMed Scopus Google Scholar). The for this is activity and HMG-CoA reductase were HMG-CoA reductase activity was which led to cholesterol synthesis and and J.J. of A reductase in Biol. Full Text PDF PubMed Google observed that reduces HMG-CoA reductase However, the that impaired synthesis reduced HMG-CoA reductase activity and not to ER stress. HMG-CoA reductase expression is by In HMG-CoA reductase by the endoplasmic pathway is an process in the of expression A.G. of endoplasmic of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, N. a with and to of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). ER stress induction is with increased activity and PERK R. E. J. C. T. A protein and the Biol. 2000; PubMed Scopus Google we that of HMG-CoA reductase by is increased under acute ER stress and to cholesterol found that HMG-CoA reductase activity was by under ER stress, cholesterol synthesis was by This be by of cholesterol other HMG-CoA of which are and be by ER stress L.J. A.J. cholesterol synthesis reductase Biol. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). ER stress affects cholesterol efflux and our data suggest that the to impaired cholesterol efflux and reduced cholesterol synthesis are not to Under conditions, reduced cholesterol efflux is to endogenous synthesis because cholesterol Under ER stress, we found increased that impaired cholesterol efflux not repress cholesterol synthesis the reduced cholesterol synthesis not ABCA1 downregulation under ER stress. we found that ABCA1 is not by and therefore cholesterol is not a main of ABCA1 expression in hepatic we not reduced ABCA1 expression we cholesterol synthesis by not is that ABCA1 is due to impaired cholesterol ER stress of ABCA1 and cholesterol 1 and ER stress trafficking from the ER to the as well as and M. R. S. D. R. P. endoplasmic reticulum stress activates the expression of receptor proteins and the to the J. Biol. 2006; PubMed Scopus Google Scholar, M. S. C. C. S. M. S. P. Endoplasmic reticulum stress reduces the from the ER and the of J. Biol. PubMed Scopus Google Scholar). ABCA1 and to the be reduced ER stress. This lead to impaired ABCA1 function. In we found that the cholesterol proteins and are not which is in with D. M. S. ER stress expression by and to of protein from the to the Lipid Res. 2012; 53: Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. A. T. K. of human gene expression under endoplasmic reticulum Res. 2006; PubMed Scopus Google Scholar, J.L. gene of and cholesterol of by sterol element-binding protein-2 and by endoplasmic reticulum Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). in and increased expression of cholesterol proteins the perinuclear accumulation of this redistribution of cholesterol is functional in of for efflux for increased activity to be Taken together, our data show severe in cellular cholesterol metabolism by ER stress. be to the of in metabolic which are with hepatic ER stress. The for for and and for for with activating transcription factor 6 protein protein endoplasmic reticulum endoplasmic endoplasmic protein glucose-regulated protein 78 of the LDL receptor inositol requiring protein 1 liver X receptor protein kinase RNA-like endoplasmic reticulum kinase scavenger receptor class B, type I sterol response element-binding protein unfolded protein response

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