Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription

Elevated serum levels of triglyceride-rich remnant lipoproteins (TRL) are a major risk factor predisposing a subject to atherosclerosis. Apolipoprotein C-III (apoC-III) is a major constituent of TRL that impedes triglyceride hydrolysis and remnant clearance and, as such, may exert pro-atherogenic activities. In the present study, transient cotransfection experiments in rat hepatocytes in primary culture and rabbit kidney RK13 cells demonstrated that overexpression of Rev-erbα specifically decreases basal and HNF-4 stimulated human apoC-III promoter activity. A Rev-erbα response element was mapped by promoter deletion, mutation analysis, and gel-shift experiments to a AGGTCA half-site located at position −23/−18 (downstream of the TATA box) in the apoC-III promoter. Finally, Rev-erbα-deficient mice displayed elevated serum and liver mRNA levels of apoC-III together with increased serum VLDL triglycerides.Taken together, our data identify Rev-erbα as a regulator of apoC-III gene expression, providing a novel, physiological role for this nuclear receptor in the regulation of lipid metabolism. Elevated serum levels of triglyceride-rich remnant lipoproteins (TRL) are a major risk factor predisposing a subject to atherosclerosis. Apolipoprotein C-III (apoC-III) is a major constituent of TRL that impedes triglyceride hydrolysis and remnant clearance and, as such, may exert pro-atherogenic activities. In the present study, transient cotransfection experiments in rat hepatocytes in primary culture and rabbit kidney RK13 cells demonstrated that overexpression of Rev-erbα specifically decreases basal and HNF-4 stimulated human apoC-III promoter activity. A Rev-erbα response element was mapped by promoter deletion, mutation analysis, and gel-shift experiments to a AGGTCA half-site located at position −23/−18 (downstream of the TATA box) in the apoC-III promoter. Finally, Rev-erbα-deficient mice displayed elevated serum and liver mRNA levels of apoC-III together with increased serum VLDL triglycerides. Taken together, our data identify Rev-erbα as a regulator of apoC-III gene expression, providing a novel, physiological role for this nuclear receptor in the regulation of lipid metabolism. Triglyceride-rich lipoprotein remnants (TRL) are positively correlated with the progression of atherosclerosis (1Hodis H.N. Triglyceride-rich lipoprotein remnant particles and risk of atherosclerosis.Circulation. 1999; 99: 2852-2854Google Scholar, 2Krauss R.M. Atherogenicity of triglyceride-rich lipoproteins.Am. J. Cardiol. 1998; 81: 13B-17BGoogle Scholar). Moreover, elevated serum triglyceride concentrations, in addition to elevated LDL-cholesterol (LDL-C) and reduced HDL-C levels, are now considered as an independent risk factor for coronary heart disease (CHD) (3Assmann G. Cullen P. Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years.Eur. Heart J. 1998; 19: A2-11Google Scholar, 4Davignon J. Cohn J.S. Triglycerides: a risk factor for coronary heart disease.Atherosclerosis. 1996; 124: S57-S64Google Scholar, 5Gotto Jr., A.M. Triglyceride: the forgotten risk factor.Circulation. 1998; 97: 1027-1028Google Scholar, 6Hokanson J.E. Austin M.A. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta- analysis of population-based prospective studies.J. Cardiovasc. Risk. 1996; 3: 213-219Google Scholar). ApoC-III is a 79-amino acid glycoprotein synthesized in the liver and intestine that plays a key role in serum triglyceride metabolism by delaying the catabolism of triglyceride-rich particles (7Shachter N.S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism.Curr. Opin. Lipidol. 2001; 12: 297-304Google Scholar, 8Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Google Scholar). Hence, apoC-III is a potential target gene for the identification of hypolipidemic drugs. ApoC-III gene expression is tightly regulated, being repressed by hormones such as insulin (9Chen M. Breslow J.L. Li W. Leff T. Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.J. Lipid Res. 1994; 35: 1918-1924Google Scholar, 10Li W.W. Dammerman M.M. Smith J.D. Metzger S. Breslow J.L. Leff T. Common genetic variation in the promoter of the human apoC-III gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.J. Clin. Invest. 1995; 96: 2601-2605Google Scholar) or thyroid hormones (11Lin-Lee Y.C. Strobl W. Soyal S. Radosavljevic M. Song M. Gotto Jr., A.M. Patsch W. Role of thyroid hormone in the expression of apolipoprotein A-IV and C- III genes in rat liver.J. Lipid Res. 1993; 34: 249-259Google Scholar), cytokines such as interleukin-1 (12Lacorte J.M. Ktistaki E. Beigneux A. Zannis V.I. Chambaz J. Talianidis I. Activation of CAAT enhancer-binding protein delta (C/EBPdelta) by interleukin-1 negatively influences apolipoprotein C-III expression.J. Biol. Chem. 1997; 272: 23578-23584Google Scholar) or tumor necrosis factor α (13Lacorte J.M. Beigneux A. Parant M. Chambaz J. Repression of apoC-III gene expression by TNFalpha involves C/EBPdelta/NF-IL6beta via an IL-1 independent pathway.FEBS Lett. 1997; 415: 217-220Google Scholar), as well as hypolipidemic drugs such as fibrates (14Haubenwallner S. Essenburg A.D. Barnett B.C. Pape M.E. DeMattos R.B. Krause B.R. Minton L.L. Auerbach B.J. Newton R.S. Leff T. Bisgaier C.L. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action.J. Lipid Res. 1995; 36: 2541-2551Google Scholar, 15Staels B. Vu-Dac N. Kosykh V.A. Saladin R. Fruchart J.C. Dallongeville J. Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.J. Clin. Invest. 1995; 95: 705-712Google Scholar), or β-blocked fatty acids (16Hertz R. Bishara-Shieban J. Bar-Tana J. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.J. Biol. Chem. 1995; 270: 13470-13475Google Scholar, 17Raspé E. Madsen L. Lefebvre A.M. Leitersdorf I. Gelman L. Peinado-Onsurbe J. Dallongeville J. Fruchart J.C. Berge R. Staels B. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.J. Lipid Res. 1999; 40: 2099-2110Google Scholar). By contrast, its expression is increased by retinoids (18Vu-Dac N. Gervois P. Torra I.P. Fruchart J.C. Kosykh V. Kooistra T. Princen H.M. Dallongeville J. Staels B. Retinoids increase human apoC-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.J. Clin. Invest. 1998; 102: 625-632Google Scholar). The apoC-III gene is located on chromosome 11q23 between the apoA-I and apoA-IV genes (19Karathanasis S.K. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes.Proc. Natl. Acad. Sci. USA. 1985; 82: 6374-6378Google Scholar). Regulatory sequences determining the tissue-specific expression pattern of apoC-III have been delineated (20Zannis V.I. Kan H.Y. Kritis A. Zanni E.E. Kardassis D. Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo.Curr. Opin. Lipidol. 2001; 12: 181-207Google Scholar). They include a distal regulatory enhancer that determines the level and tissue specificity of expression of apoC-III, apoA-I, and apoA-IV, as well as a proximal promoter. The C3P located in the proximal promoter plays a key role in the of apoC-III promoter activity. a of by to the nuclear and the and that as well and that apoC-III promoter activity. The proximal promoter for and a of the acid receptor receptor of nuclear as a physiological transcriptional of apoC-III gene expression E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar). at response located at the C3P and −23/−18 (downstream of the TATA box) in the apoC-III promoter. plays a role in is between the and human apoC-III gene promoter Finally, in the of the apoC-III promoter by and to the between and HNF-4 between the TATA and the C3P D. J.M. Chambaz J. P. A. are for the of the human apolipoprotein C-III promoter by factor and hepatic nuclear Biol. Chem. Scholar). The are a of nuclear of Rev-erbα or and or the of are V. nuclear gene to 1999; Scholar). The Rev-erbα gene is located on human chromosome and on the of the receptor N. R. S. T. with are of the genetic Scholar, M.A. W.W. A of the hormone receptor is by the of the rat transcriptional Biol. Scholar, V. A. A. P. D. S. organization of the human thyroid hormone receptor Res. 19: Scholar). to M.A. The receptor via a response Biol. 1993; Scholar), as a of M.A. The receptor as a on a Biol. 1995; Scholar). Rev-erbα as to response of the by a M.A. The receptor via a response Biol. 1993; Scholar, J. B. R. R.M. and the of nuclear 1994; Scholar) or as on response of a tandem of by and by a M.A. The receptor as a on a Biol. 1995; Scholar, G. A. D. V. A functional element located in the human promoter a Natl. Acad. Sci. USA. 1996; Scholar). Rev-erbα is in J. B. R. R.M. and the of nuclear 1994; Scholar) and liver J. B. R. R.M. and the of nuclear 1994; Scholar, P. S. A. G. Kosykh V. Fruchart J.C. J. V. Staels B. Fibrates increase human expression in liver via a peroxisome receptor response 1999; Scholar). of Rev-erbα is in rat liver to fibrates P. S. A. G. Kosykh V. Fruchart J.C. J. V. Staels B. Fibrates increase human expression in liver via a peroxisome receptor response 1999; Scholar) is liver to I.P. V. Saladin R. V. Fruchart J.C. Kosykh V. Staels B. and regulation of expression in Scholar). on the of response in their promoter and on in vitro target genes for G. A. D. V. A functional element located in the human promoter a Natl. Acad. Sci. USA. 1996; Scholar, M. expression of the and the expression of the gene 1995; Scholar, I. V. regulation of the by and of the of nuclear hormone Biol. 1997; Scholar, A. nuclear hormone receptor expression the promoter of the gene by peroxisome receptor Biol. Chem. 1999; Scholar, B. H. W. N. V. V. J.L. Modulation of the enhancer of the rat gene by of the and of nuclear Biol. 19: Scholar, N. S. Gervois P. E. G. Fruchart J.C. V. Staels B. The nuclear peroxisome receptor and the regulation of apolipoprotein expression by fibrates.J. Biol. Chem. 1998; Scholar). A been that a Rev-erbα gene and in P. I. A. E. L. B. E. and in the of mice the Scholar). Rev-erbα was to to response as with on the of between nuclear receptor J. B. R. R.M. and the of nuclear 1994; Scholar). that the response element in the human and apoC-III gene promoter a target for A in basal and activity of the human apoC-III promoter was of The Rev-erbα response element was located at the −23/−18 AGGTCA half-site of the TATA that is in action data are in with this was in H. J.C. nuclear hormone receptor the human apolipoprotein Biol. Chem. Scholar). In an increase in serum and liver mRNA levels of apoC-III that elevated in Rev-erbα-deficient Taken together, data identify Rev-erbα as a novel, physiological regulator of apoC-III The or the human apoC-III gene promoter in of the gene E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar). The was a of A. The to the gene the of the promoter and enhancer was E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar). The and by V. and B. hepatocytes by of to E. Madsen L. Lefebvre A.M. Leitersdorf I. Gelman L. Peinado-Onsurbe J. Dallongeville J. Fruchart J.C. Berge R. Staels B. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.J. Lipid Res. 1999; 40: 2099-2110Google Scholar). in with by fatty and insulin the culture was to the and with expression and the the was and cells with and for in as the of the the cells with and the activity was with the to the experiments at of the was by the the RK13 in culture with serum at in a of was in at a of and at for to the lipid as E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar) with expression and the the of the the cells with and gene activity was as Rev-erbα was in vitro the and the the as E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar). and and as and of by to of and Rev-erbα-deficient mice in a as P. I. A. E. L. B. E. and in the of mice the Scholar) The mice a the was a was by at for at at and for serum apoC-III, and lipoprotein the mice and tissue on and at apoC-III levels by an a as Peinado-Onsurbe J. Fruchart J.C. A. Auwerx J. serum triglyceride levels of apolipoprotein C-III and lipoprotein Lett. 1999; Scholar). triglyceride by triglyceride by protein and triglyceride in the as J.M. N. Staels B. Fruchart J.C. Auwerx J. in lipoprotein metabolism in peroxisome receptor Biol. Chem. 1997; 272: Scholar). and as B. Vu-Dac N. Kosykh V.A. Saladin R. Fruchart J.C. Dallongeville J. Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.J. Clin. Invest. 1995; 95: 705-712Google Scholar). that is a physiological regulator of hepatic apoC-III E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar). In to is in the of the human apoC-III transient experiments In primary rat cotransfection of a human expression in a activity of a gene by the of the human apoC-III promoter A of apoC-III promoter activity was in rabbit kidney RK13 cells The of overexpression was as the was in The of on the of expression In addition to of the nuclear receptor apoC-III gene promoter activity (20Zannis V.I. Kan H.Y. Kritis A. Zanni E.E. Kardassis D. Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo.Curr. Opin. Lipidol. 2001; 12: 181-207Google Scholar). In to the to overexpression influences the action of such RK13 cells with a by the of the apoC-III gene promoter in the of a of expression and of expression of reduced the activity of the gene in a with Rev-erbα negatively with the of the human apoC-III gene promoter by RK13 cells with the and with of the expression in the or of of the expression and activity and as in and identify the response for of the apoC-III of this promoter with the expression in RK13 as E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar), of the promoter to a in its basal activity the was repressed by that the of the apoC-III promoter are to identify sequences to to of the of the apoC-III promoter as in protein as was on the of the apoC-III gene promoter the AGGTCA half-site by an that to E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar). of to the of the apoC-III promoter was mutation of the AGGTCA half-site present in position −23/−18 The of to the of the apoC-III promoter was by of a that of the was by of the by of the Taken together, our the of a for on the proximal human apoC-III of the TATA to the of the human apoC-III promoter. to the or of the apoC-III promoter as with in vitro protein or as and as in and In in vitro protein or with and of to a Rev-erbα response element the addition of the with are by an this response element is functional in the of the proximal apoC-III the AGGTCA half-site present of the TATA in position −23/−18 of the apoC-III promoter was by in the mutation the basal activity of the apoC-III promoter in rat hepatocytes and In RK13 this mutation in a of the data that the −23/−18 half-site plays the major role in the of the apoC-III promoter in hepatocytes and RK13 of the response element present in the of the human apoC-III promoter in RK13 RK13 cells with expression or the as and the or a of the human apoC-III promoter in of the gene The was as RK13 cells with expression and of the or the of the human apoC-III promoter in of the promoter of the gene as in and activity and as in and the −23/−18 half-site Rev-erbα to a the of the apoC-III promoter was in of a The activity of RK13 cells with the was repressed by the specificity of the was with a expression in RK13 In to the the activity RK13 cells with the was by that the of the apoC-III promoter of the apoC-III promoter the of the apoC-III in of a The activity of RK13 cells with and the expression was by data that the AGGTCA half-site to in the proximal human apoC-III promoter is functional in the of a promoter and that the of the apoC-III promoter an response Rev-erbα plays a physiological role in the regulation of apoC-III expression, apoC-III levels between Rev-erbα-deficient and mice P. I. A. E. L. B. E. and in the of mice the Scholar). apoC-III mRNA levels increased in hepatic mRNA levels as in Rev-erbα-deficient mice a increase in apoC-III to Finally, this increase in apoC-III was with a increase in serum triglyceride levels that to to the VLDL as by data that serum are increased in Rev-erbα-deficient mice data the that Rev-erbα as a physiological regulator of apoC-III TRL are considered major risk to the of atherosclerosis (1Hodis H.N. Triglyceride-rich lipoprotein remnant particles and risk of atherosclerosis.Circulation. 1999; 99: 2852-2854Google Scholar, 2Krauss R.M. Atherogenicity of triglyceride-rich lipoproteins.Am. J. Cardiol. 1998; 81: 13B-17BGoogle Scholar). apoC-III is a major of serum triglyceride and remnant lipoprotein metabolism (7Shachter N.S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism.Curr. Opin. Lipidol. 2001; 12: 297-304Google Scholar, 8Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Google Scholar), apoC-III gene is a to serum of In the present Rev-erbα as a of apoC-III promoter activity. A Rev-erbα response element was located in the −23/−18 position of the human apoC-III data are in with in vitro by H. J.C. nuclear hormone receptor the human apolipoprotein Biol. Chem. Scholar) this was in with the response element E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar), of a AGGTCA half-site by an that the by a in position M.A. The receptor via a response Biol. 1993; Scholar). that this is in the of a promoter. in the rat apoA-I and apoC-III the human apoC-III response element is located of the TATA the to and Rev-erbα to the that the apoC-III response in a with a functional to of by Rev-erbα or involves with and the of a response element of the TATA is a The increase in serum apoC-III and in liver apoC-III mRNA levels of Rev-erbα-deficient mice as to mice that Rev-erbα apoC-III gene expression in that the of Rev-erbα on apoC-III gene expression is and the data by to the in H. J.C. nuclear hormone receptor the human apolipoprotein Biol. Chem. Scholar). apoC-III plays an important role in triglyceride metabolism (7Shachter N.S. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism.Curr. Opin. Lipidol. 2001; 12: 297-304Google Scholar, 8Jong M.C. Hofker M.H. Havekes L.M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Google Scholar), genes contribute to the of their or and serum triglyceride are to in addition to its on apoC-III expression, Rev-erbα serum triglyceride metabolism via such the of the of the human apoC-III promoter that Rev-erbα is in the promoter J.L. N. A. Breslow J.L. of the apolipoprotein gene and protein sequences with to Scholar), is that Rev-erbα plays a role as physiological of apoC-III expression in The receptor of Rev-erbα and that response J. B. R. R.M. and the of nuclear 1994; Scholar). that human human apoC-III promoter activity serum apoC-III in Rev-erbα-deficient mice that is to for are in the liver J. B. R. R.M. and the of nuclear 1994; Scholar). is that mice an The apoC-III gene is located on chromosome 11q23 between the apoA-I and apoA-IV genes (19Karathanasis S.K. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes.Proc. Natl. Acad. Sci. USA. 1985; 82: 6374-6378Google Scholar). the major protein constituent of and apoA-IV, present in A. H. to plasma Scholar), are in cholesterol and have a on atherosclerosis mechanisms of 1999; Scholar). to the of apoA-I and apoA-IV at apoC-III levels negatively apoA-I and apoA-IV rat apoA-I gene expression N. Gervois P. T. P. Fruchart J.C. Auwerx J. J. A. Staels B. Transcriptional regulation of apolipoprotein gene expression by the nuclear receptor Biol. Chem. 1997; 272: Scholar), Rev-erbα via the response the is in the human apoA-I promoter N. S. Gervois P. E. G. Fruchart J.C. V. Staels B. The nuclear peroxisome receptor and the regulation of apolipoprotein expression by fibrates.J. Biol. Chem. 1998; Scholar). human apoA-I promoter activity by or Rev-erbα E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar, N. S. Gervois P. E. G. Fruchart J.C. V. Staels B. The nuclear peroxisome receptor and the regulation of apolipoprotein expression by fibrates.J. Biol. Chem. 1998; Scholar). the of the apoC-III promoter activity by Rev-erbα is and basal activity of the human apoC-III promoter in rat hepatocytes is increased the Rev-erbα response element is our that Rev-erbα is a target that the human apoC-III expression on human apoA-I Fibrates or β-blocked fatty acids that are hypolipidemic drugs in the of In addition to to apoC-III expression in and in vitro (14Haubenwallner S. Essenburg A.D. Barnett B.C. Pape M.E. DeMattos R.B. Krause B.R. Minton L.L. Auerbach B.J. Newton R.S. Leff T. Bisgaier C.L. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action.J. Lipid Res. 1995; 36: 2541-2551Google Scholar, 15Staels B. Vu-Dac N. Kosykh V.A. Saladin R. Fruchart J.C. Dallongeville J. Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.J. Clin. Invest. 1995; 95: 705-712Google Scholar, R. Bishara-Shieban J. Bar-Tana J. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.J. Biol. Chem. 1995; 270: 13470-13475Google Scholar, 17Raspé E. Madsen L. Lefebvre A.M. Leitersdorf I. Gelman L. Peinado-Onsurbe J. Dallongeville J. Fruchart J.C. Berge R. Staels B. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.J. Lipid Res. 1999; 40: 2099-2110Google Scholar). The mechanism by fibrates downregulate apoC-III gene is involves J.M. N. Staels B. Fruchart J.C. Auwerx J. in lipoprotein metabolism in peroxisome receptor Biol. Chem. 1997; 272: Scholar). to the C3P of the proximal human apoC-III promoter (16Hertz R. Bishara-Shieban J. Bar-Tana J. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.J. Biol. Chem. 1995; 270: 13470-13475Google Scholar). this in of a is by in the of their (18Vu-Dac N. Gervois P. Torra I.P. Fruchart J.C. Kosykh V. Kooistra T. Princen H.M. Dallongeville J. Staels B. Retinoids increase human apoC-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.J. Clin. Invest. 1998; 102: 625-632Google Scholar). the of fibrates on apoC-III gene is and that HNF-4 expression is reduced and that with of HNF-4 to the C3P the activity of this (16Hertz R. Bishara-Shieban J. Bar-Tana J. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.J. Biol. Chem. 1995; 270: 13470-13475Google Scholar). regulation of HNF-4 expression by fibrates N. S. Gervois P. E. G. Fruchart J.C. V. Staels B. The nuclear peroxisome receptor and the regulation of apolipoprotein expression by fibrates.J. Biol. Chem. 1998; Scholar). Rev-erbα expression is by fibrates via a element in the Rev-erbα gene promoter P. S. A. G. Kosykh V. Fruchart J.C. J. V. Staels B. Fibrates increase human expression in liver via a peroxisome receptor response 1999; Scholar), our that may apoC-III gene at in by liver Rev-erbα gene are to ApoC-III gene promoter activity is by a of in nuclear (20Zannis V.I. Kan H.Y. Kritis A. Zanni E.E. Kardassis D. Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo.Curr. Opin. Lipidol. 2001; 12: 181-207Google Scholar). been to a regulator of hepatic apoC-III to the response element in the apoC-III promoter as Rev-erbα E. H. Gervois P. Fruchart J.C. S. J. A. Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the nuclear receptor Biol. Chem. 2001; Scholar), that the activity levels of a apoC-III Moreover, Rev-erbα decreases apoC-III promoter by the nuclear receptor a key regulator of apoC-III that to in the promoter (20Zannis V.I. Kan H.Y. Kritis A. Zanni E.E. Kardassis D. Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo.Curr. Opin. Lipidol. 2001; 12: 181-207Google Scholar). a role of Rev-erbα in apoC-III Hence, the between nuclear receptor important for the of In the the expression of rat apoA-I is by N. Gervois P. T. P. Fruchart J.C. Auwerx J. J. A. Staels B. Transcriptional regulation of apolipoprotein gene expression by the nuclear receptor Biol. Chem. 1997; 272: Scholar) and Rev-erbα N. S. Gervois P. E. G. Fruchart J.C. V. Staels B. The nuclear peroxisome receptor and the regulation of apolipoprotein expression by fibrates.J. Biol. Chem. 1998; Scholar). action of of a role in the of the predisposing to atherosclerosis as with A. S. B. M. N. G. Staels B. N. J. A. atherosclerosis and in the a of the nuclear receptor 1998; Scholar). been for The of an in the that is that such V. nuclear gene to 1999; Scholar). Hence, its activity by its expression level or by of the mechanisms its expression or via of to identify serum triglyceride In our that human apoC-III promoter activity is by and that Rev-erbα-deficient mice increased liver mRNA and serum apoC-III levels identify Rev-erbα as a of apoC-III expression in mice and data that a target for the of The B. E. J. and for The A. B. and V. for providing and G. for the lipid was by the the the the and the was by the