Estrogen-related Receptor α (ERRα) Is a Transcriptional Regulator of Apolipoprotein A-IV and Controls Lipid Handling in the Intestine

The estrogen-related receptor α (ERRα) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRα induces a high energy expenditure in the presence of the coactivator PGC-1α. However, ERRα knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRα is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRα plays a function in dietary energy handling. Gene expression profiling in the intestine identified a subset of genes involved in oxidative phosphorylation that were down-regulated in the absence of ERRα. In support of the physiological role of ERRα in this pathway, isolated enterocytes from ERRα knockout mice display lower capacity for β-oxidation. Microarray results also show altered expression of genes involved in dietary lipid digestion and absorption, such as pancreatic lipase-related protein 2 (PLRP2), fatty acid-binding protein 1 and 2 (L-FABP and I-FABP), and apolipoprotein A-IV (apoA-IV). In agreement, we found that ERRα–/– pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRα and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRα, in cooperation with PGC-1α, activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. Our results demonstrate that apoA-IV is a direct ERRα target gene and suggest a function for ERRα in intestinal fat transport, a crucial step in energy balance. The estrogen-related receptor α (ERRα) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRα induces a high energy expenditure in the presence of the coactivator PGC-1α. However, ERRα knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRα is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRα plays a function in dietary energy handling. Gene expression profiling in the intestine identified a subset of genes involved in oxidative phosphorylation that were down-regulated in the absence of ERRα. In support of the physiological role of ERRα in this pathway, isolated enterocytes from ERRα knockout mice display lower capacity for β-oxidation. Microarray results also show altered expression of genes involved in dietary lipid digestion and absorption, such as pancreatic lipase-related protein 2 (PLRP2), fatty acid-binding protein 1 and 2 (L-FABP and I-FABP), and apolipoprotein A-IV (apoA-IV). In agreement, we found that ERRα–/– pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRα and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRα, in cooperation with PGC-1α, activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. Our results demonstrate that apoA-IV is a direct ERRα target gene and suggest a function for ERRα in intestinal fat transport, a crucial step in energy balance. Nuclear receptors are ligand-inducible transcription factors that control important metabolic pathways needed for development and homeostasis. This superfamily includes classic receptors for ligands such as steroid hormones, vitamin D, and thyroid hormones as well as orphan nuclear receptors for which there are no physiological ligands associated at the time of their discovery (1Giguère V. Endocr. Rev. 1999; 20: 689-725Crossref PubMed Scopus (720) Google Scholar). Estrogen-related receptor α (ERRα) 1The abbreviations used are: ERR, estrogen-related receptor; apo, apolipoprotein; ChIP, chromatin immunoprecipitation; PGC-1α, peroxisome proliferator-activated receptor α coactivator 1α; PPAR, peroxisome proliferator-activated receptor; FABP, fatty acid-binding protein; Ab, antibody. is an orphan nuclear receptor originally identified on the basis of its homology with the estrogen receptor α (2Giguère V. Yang N. Segui P. Evans R.M. Nature. 1988; 331: 91-94Crossref PubMed Scopus (700) Google Scholar). The two receptors display transcriptional cross-talk and share some target genes and synthetic ligands (reviewed in Ref. 3Giguère V. Trends Endocrinol. Metab. 2002; 13: 220-225Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar). Furthermore, ERRα may have a function in bone remodeling (4Bonnelye E. Merdad L. Kung V. Aubin J.E. J. Cell Biol. 2001; 153: 971-984Crossref PubMed Scopus (112) Google Scholar, 5Bonnelye E. Kung V. Laplace C. Galson D.L. Aubin J.E. Endocrinology. 2002; 143: 3658-3670Crossref PubMed Scopus (54) Google Scholar) and as a prognostic marker of breast cancer (6Ariazi E.A. Clark G.M. Mertz J.E. Cancer Res. 2002; 62: 6510-6518PubMed Google Scholar, 7Suzuki T. Miki Y. Moriya T. Shimada N. Ishida T. Hirakawa H. Ohuchi N. Sasano H. Cancer Res. 2004; 64: 4670-4676Crossref PubMed Scopus (195) Google Scholar), two classical estrogen-responsive tissues. Apart from its proposed role as a modulator of estrogen receptor-dependent pathways, several lines of evidence indicate that ERRα acts primarily as a regulator of energy metabolism. First, ERRα is known to be expressed in tissues with high β-oxidation activity such as the brown fat, kidney, heart, and intestine (2Giguère V. Yang N. Segui P. Evans R.M. Nature. 1988; 331: 91-94Crossref PubMed Scopus (700) Google Scholar, 8Vanacker J.M. Delmarre C. Guo X. Laudet V. Cell Growth Differ. 1998; 9: 1007-1014PubMed Google Scholar, 9Sladek R. Bader J.-A. Giguère V. Mol. Cell. Biol. 1997; 17: 5400-5409Crossref PubMed Google Scholar). Furthermore, ERRα expression is induced during adipocyte differentiation (10Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 12378-12383Crossref PubMed Scopus (309) Google Scholar) and in response to stimuli that increase energy demand such as in the liver under fasting conditions (11Ichida M. Nemoto S. Finkel T. J. Biol. Chem. 2002; 277: 50991-50995Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) and in skeletal muscle and brown fat from mice exposed to cold (12Schreiber S.N. Knutti D. Brogli K. Uhlmann T. Kralli A. J. Biol. Chem. 2003; 278: 9013-9018Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar). Second, ERRα regulates the gene encoding medium chain acyl-CoA dehydrogenase (MCAD), which catalyzes the initial step in mitochondrial fatty acid β-oxidation (9Sladek R. Bader J.-A. Giguère V. Mol. Cell. Biol. 1997; 17: 5400-5409Crossref PubMed Google Scholar, 13Vega R.B. Kelly D.P. J. Biol. Chem. 1997; 272: 31693-31699Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 14Huss J.M. Kopp R.P. Kelly D.P. J. Biol. Chem. 2002; 277: 40265-40274Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar). Third, the peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α), a coactivator central to the control of energy expenditure (15Puigserver P. Spiegelman B.M. Endocr. Rev. 2003; 24: 78-90Crossref PubMed Scopus (1640) Google Scholar), has recently been described as a key partner of ERRα, assuring both its expression and transactivation potential (10Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 12378-12383Crossref PubMed Scopus (309) Google Scholar, 11Ichida M. Nemoto S. Finkel T. J. Biol. Chem. 2002; 277: 50991-50995Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 12Schreiber S.N. Knutti D. Brogli K. Uhlmann T. Kralli A. J. Biol. Chem. 2003; 278: 9013-9018Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 14Huss J.M. Kopp R.P. Kelly D.P. J. Biol. Chem. 2002; 277: 40265-40274Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 16Laganiere J. Tremblay G.B. Dufour C.R. Giroux S. Rousseau F. Giguere V. J. Biol. Chem. 2004; 279: 18504-18510Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). In fact, ERRα appears to be an essential transducer of PGC-1α action in mediating mitochondrial biogenesis (17Schreiber S.N. Emter R. Hock M.B. Knutti D. Cardenas J. Podvinec M. Oakeley E.J. Kralli A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 6472-6477Crossref PubMed Scopus (515) Google Scholar, 18Mootha V.K. Handschin C. Arlow D. Xie X. St Pierre J. Sihag S. Yang W. Altshuler D. Puigserver P. Patterson N. Willy P.J. Schulman I.G. Heyman R.A. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar). We recently that the absence of ERRα in knockout mice to reduced fat mass and to high fat diet-induced J. R. J. Bader J.-A. D. Giguère V. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). In gene expression profiling in from ERRα knockout mice in the expression of genes in the regulation of and energy metabolism. However, we not significant in dietary energy expenditure the and mice. that ERRα is expressed in the intestine, of dietary in mice also to the In fact, the intestine is the essential for the of the the are the in which a of in their as In the intestine to β-oxidation because of its and T. M. T. T. J. Res. 2002; Full Text Full Text PDF PubMed Google Scholar). In the we have the role of ERRα in intestinal the ERRα knockout mice and the of gene expression Our show that ERRα is involved in mitochondrial and intestinal lipid handling. In particular, ERRα with the apolipoprotein enhancer and regulates the apoA-IV mice were as described J. R. J. Bader J.-A. D. Giguère V. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). used were were under conditions in the of the and were and mice were the of of were 2 from tissues and to were used as to apoA-IV expression gene expression were mice as well as ERRα–/– and mice. in tissues from mice were in and in were for in to with a from the of ERRα control with a were isolated from the of mice an of a described N. Cell Res. 1998; PubMed Scopus Google Scholar). mice were and the of and and with cold The were further in and in of cold at for The epithelial The epithelial and with cold Nuclear were isolated from the epithelial as described (9Sladek R. Bader J.-A. Giguère V. Mol. Cell. Biol. 1997; 17: 5400-5409Crossref PubMed Google Scholar). were on to a and with ERRα the of ERRα J. R. J. Bader J.-A. D. Giguère V. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar) and The were with an to of the and from intestinal tissues were with the with on from mice of to gene expression in in of the in of the and in both and of the The used for gene expression profiling This is on the from the Microarray of from ERRα–/– and mice intestinal tissues were with on at the on 2 a such as the ERRα–/– with for and with for the were the and the and the expression for gene were as the of the of in ERRα–/– that of the were to a with and of 2 were genes were as genes found to be expressed in of of from of the used for were used to in and were used as and and were on from the The of the and on of the the the as a function of J. Mol. Endocrinol. PubMed Scopus Google Scholar). The for gene of the of the target gene and that of the gene in ERRα–/– and and for the Res. 2001; PubMed Scopus Google Scholar). are the of and were in in epithelial cells from mice for were isolated as described in the and on with of 1 and The at for and the used for β-oxidation as T. M. T. T. J. Res. 2002; Full Text Full Text PDF PubMed Google Scholar). the β-oxidation 2 2 1 of of protein of in a of The the protein and the at for The of the at time were in The with of to The in the The in were in protein described for lipid L. D. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), of from and mice of the were with a small of and for 1 in a at The with 2 of for at a 1 and to a of with The with 1 of and the to The in 2 of and to The and the to a in a at The in the and the the lipid the lipid which expressed as a of the of the from were and the The from several and as for The of the to as and the were with The of and Cell the protein ERRα of the transcriptional of the The from A. Kralli cells were a from J. F. and cells were from the were in essential medium and to the cells were in of of of and of control of of of as in the The cells The cells were in a were as described M. Giguère V. PubMed Scopus Google Scholar). The were to the activity of results in at were as described J. Giguère V. in Scholar). 1 cells were with of for at were with and were in with for and for a at to the chromatin in chromatin 2 and the J. Tremblay G.B. Dufour C.R. Giroux S. Rousseau F. Giguere V. J. Biol. Chem. 2004; 279: 18504-18510Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) the of and for 2 The were for with 1 2 and 1 were with and with The were and at for at The isolated were to and The were apoC-III and apoC-III and and of a control of ERRα with the of and we used of the ERRα promoter as described J. Tremblay G.B. Dufour C.R. Giroux S. Rousseau F. Giguere V. J. Biol. Chem. 2004; 279: 18504-18510Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). ERRα in the first used to the expression of ERRα the intestinal of mice. in ERRα expression is to epithelial cells with with nuclear from epithelial cells isolated from mice the and at the development to the presence of the ERRα ERRα expression in the small intestine from with lower in mice In ERRα expressed in epithelial cells involved in such as and of the of ERRα were in the and for ERRα Gene with in the in function of ERRα in the intestine, we of the described mice J. R. J. Bader J.-A. D. Giguère V. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). intestinal tissues from mice were not we first to intestinal gene expression associated with ERRα is a in gene expression intestinal tissues from mice were Furthermore, to expressed genes to both and in we in mice of in the and and in the genes found to be expressed were the absence of ERRα expression in mice a of genes involved in mitochondrial were down-regulated in the intestine from mice. This includes dehydrogenase and the and both needed to to in to an as well as the the mitochondrial is for oxidative is known to be involved in mitochondrial biogenesis and We found PGC-1α to be in the intestine from with mice PGC-1α not identified as expressed in not This of has been and be important M. J. A. A. L. W. M. J. Res. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). chain is to the mitochondrial β-oxidation and of the results in of the S. K. M. J. PubMed Scopus Google Scholar). the physiological of ERRα on intestinal lipid we the β-oxidation activity in intestinal epithelial cells isolated from ERRα–/– and mice. in for ERRα is associated with a significant in intestinal acid expressed genes in the intestine of ERRα receptor mitochondrial dehydrogenase lipase-related protein acid-binding protein acid-binding protein member member in a in the of in as as in results also expression in a of genes involved in dietary lipid the expression of pancreatic lipase-related protein 2 found to be expressed at lower in the intestine from mice. The expression of fatty acid-binding 1 and 2 (L-FABP and were also reduced in mice. are the high and of for chain fatty J. Biol. Chem. Full Text PDF PubMed Google Scholar). is expressed in the liver and small intestine but is to the intestinal apoA-IV also down-regulated in the to ERRα mice. is a of such as and high the apoA-IV is fat and the of M. T. P. Biol. 2003; PubMed Scopus Google Scholar). the of ERRα on the in regulation of apoA-IV gene mice were to a lipid to intestinal apoA-IV gene The results in demonstrate that ERRα–/– mice display a lower basal and apoA-IV with mice. the of apoA-IV lipid and ERRα–/– mice and and mice on high fat from and are known to have with physiological fat and we not dietary fat in pups at a of of fat pups A-IV a of human and and apoA-IV genes are a the gene the and genes are in the the apoC-III gene is in the the a for two In the expression of the apoA-IV gene in the intestine is under the control of the promoter of the apoA-IV gene with the enhancer of the apoC-III gene J. V. C. V. J. M. P. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). This enhancer has also been to direct the intestinal expression of the genes of the J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). there is some of the human and the of in the apoA-IV promoter are not well described in mice. of the the of several potential the its a first step in the of the in of a The capacity of ERRα to this the expression in in the induced a apoA-IV This that ERRα with the apoA-IV Furthermore, of ERRα with the coactivator PGC-1α results in of the the required for ERRα of the were to and with ERRα, both ERRα and PGC-1α. in of the apoA-IV to to and to ERRα in the presence of PGC-1α. This to the well apoC-III The of the apoA-IV promoter to ERRα. ERRα response be found in both the apoC-III promoter and enhancer we to the required for ERRα action on apoA-IV were in which of the apoA-IV promoter were in of the promoter to the with as well as ERRα in the presence of PGC-1α indicate that the apoC-III to is for the ERRα regulation of the apoA-IV gene Furthermore, we that a to the apoC-III enhancer to to ERRα. because of the homology the human and mice we whether ERRα also with the human apoC-III in the chromatin in cells human ERRα, a human cancer used in the of intestinal apolipoprotein metabolism. in the with a human in an for the to the human apoC-III enhancer lower of also for the apoC-III However, the two are and of the apoC-III promoter in chromatin for the apoC-III enhancer is support that ERRα with the apoC-III enhancer and the expression of intestinal apoA-IV via this In this we used of the ERRα gene in mice in with the of to the function of ERRα in the small this we in the role of ERRα in the regulation of intestinal energy and dietary lipid Furthermore, this to apoA-IV as a ERRα target gene involved in the and of We that ERRα expressed in intestinal of the mice (9Sladek R. Bader J.-A. Giguère V. Mol. Cell. Biol. 1997; 17: 5400-5409Crossref PubMed Google Scholar). further the role of ERRα in the intestine, we the of ERRα the We that ERRα gene expression to epithelial cells of intestinal and that the small intestine of ERRα with the and suggest a role for ERRα in dietary Furthermore, the high of ERRα in and of the energy from fat, support a function for ERRα in the regulation of intestinal lipid metabolism. This is in with a that ERRα regulates the medium chain dehydrogenase gene involved in fatty acid β-oxidation (9Sladek R. Bader J.-A. Giguère V. Mol. Cell. Biol. 1997; 17: 5400-5409Crossref PubMed Google Scholar, 13Vega R.B. Kelly D.P. J. Biol. Chem. 1997; 272: 31693-31699Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 14Huss J.M. Kopp R.P. Kelly D.P. J. Biol. Chem. 2002; 277: 40265-40274Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar). role for ERRα in metabolic control also the that ERRα–/– mice display a associated with reduced and high fat diet-induced J. R. J. Bader J.-A. D. Giguère V. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). However, the that mice not display lower energy expenditure a to a in intestinal of dietary that the intestine is the first in the chain of energy metabolism. We the in mice and not However, gene expression profiling a subset of genes down-regulated in the intestine from to In particular, ERRα the expression of genes involved in oxidative phosphorylation such as and dehydrogenase and Furthermore, that epithelial cells from mice ERRα a lower capacity for β-oxidation cells ERRα. β-oxidation is to oxidative are in of the in role of ERRα in oxidative phosphorylation and energy This of genes has also been found to be induced PGC-1α in cells (17Schreiber S.N. Emter R. Hock M.B. Knutti D. Cardenas J. Podvinec M. Oakeley E.J. Kralli A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 6472-6477Crossref PubMed Scopus (515) Google Scholar) and V.K. Handschin C. Arlow D. Xie X. St Pierre J. Sihag S. Yang W. Altshuler D. Puigserver P. Patterson N. Willy P.J. Schulman I.G. Heyman R.A. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar). ERRα required for PGC-1α of oxidative phosphorylation genes of cells with for ERRα reduced the of PGC-1α to genes (17Schreiber S.N. Emter R. Hock M.B. Knutti D. Cardenas J. Podvinec M. Oakeley E.J. Kralli A. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 6472-6477Crossref PubMed Scopus (515) Google Scholar). Furthermore, with an ERRα synthetic the regulation of and as well as V.K. Handschin C. Arlow D. Xie X. St Pierre J. Sihag S. Yang W. Altshuler D. Puigserver P. Patterson N. Willy P.J. Schulman I.G. Heyman R.A. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar). This PGC-1α and ERRα is with that PGC-1α ERRα via a J. Tremblay G.B. Dufour C.R. Giroux S. Rousseau F. Giguere V. J. Biol. Chem. 2004; 279: 18504-18510Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). However, lower energy in the intestine in the mice are In fact, the mice be as the is in to the of the muscle and PGC-1α and mice (10Kamei Y. Ohizumi H. Fujitani Y. Nemoto T. Tanaka T. Takahashi N. Kawada T. Miyoshi M. Ezaki O. Kakizuka A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 12378-12383Crossref PubMed Scopus (309) Google Scholar, J. H. O. Puigserver P. E. R. Spiegelman B.M. Nature. 2002; PubMed Scopus Google Scholar). is that energy is not to the mice. the that the energy from to the of the of physiological that pups dietary as This not in ERRα–/– because of to the of the small fat the lower of pups with In in dietary lipid absorption, reduced protein activity in the of E. Google Scholar, S. M. U. S. N. A. R.P. R. E. J. 2003; PubMed Scopus Google Scholar) also to to high fat diet-induced in mice. is that the of genes down-regulated in the intestine from ERRα–/– mice a role in dietary fat digestion and is of the gene from gene and is the pancreatic in mice D. J. 2004; PubMed Scopus Google Scholar). In to the is well expressed in the small intestine and its role in and digestion is the dietary fat in mice L. D. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, and are found to be expressed at lower in the intestine from ERRα–/– mice with mice. is that the and of fatty In have been to fatty F. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), as well as to gene expression fatty to the as ligands for C. T. F. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). In gene expression appears to be some fatty and H. P. A. P. J. 1997; PubMed Google Scholar, H. O. C. P. T. W. P. J. 2001; PubMed Scopus Google Scholar). 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In the ERRα–/– the of intestinal apoA-IV to fat be the of lipid malabsorption. the and of the of apoA-IV and human of fat are associated with lower of apoA-IV (reviewed in In the we that mice for ERRα lower intestinal apoA-IV gene expression in the fasting but apoA-IV fat This that ERRα not apoA-IV response to but is essential for of basal apoA-IV intestinal expression is to intestinal and In the intestine, the transcriptional regulation of the apoA-IV gene a promoter and a enhancer in the promoter of the apoC-III Our that ERRα with the apoC-III enhancer with in the presence of the PGC-1α Furthermore, we used a in the cells to demonstrate that ERRα in to the human enhancer a physiological of this transcriptional control in the transcription factors and nuclear receptors have been in to with the human apoC-III enhancer A. E. D. 2001; PubMed Google Scholar). Furthermore, the nuclear receptor has been found to be a regulator of both human and mice apoC-III via a response in the apoC-III enhancer T. Y. O. D. V. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In a has demonstrate that liver receptors both human and apoA-IV gene expression in the liver but not in the intestine Y. R. H. S. Mol. Endocrinol. 2004; PubMed Scopus Google Scholar). the direct regulation interaction in and in the apoA-IV promoter and in the apoC-III In the ERRα knockout mice in with intestinal we identified genes involved in two oxidative phosphorylation and dietary lipid digestion and The first is in with the known function of ERRα in energy expenditure PGC-1α, and the to a function for ERRα in energy from fat, a crucial first step in energy balance. Furthermore, we the apoA-IV gene as a direct ERRα target the ERRα with the apoC-III enhancer in both mice and The role of ERRα in dietary lipid be during the development of ERRα ligands P.J. J. R. R. S. P. P. R.A. Heyman R.A. Schulman I.G. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar). We and for

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