Estrogen-related receptor alpha (ERRalpha) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine.
The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRalpha induces a high energy expenditure in the presence of the coactivator PGC-1alpha. However, ERRalpha knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRalpha is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRalpha 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 ERRalpha. In support of the physiological role of ERRalpha in this pathway, isolated enterocytes from ERRalpha knockout mice display lower capacity for beta-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 ERRalpha-/- pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRalpha and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRalpha, in cooperation with PGC-1alpha, 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 ERRalpha target gene and suggest a function for ERRalpha in intestinal fat transport, a crucial step in energy balance.
Molecular Oncology Group, McGill University Health Center, Montréal, Québec H3A 1A1, Canada.
Julie C
JC
Carrier
Geneviève
G
Deblois
Céline
C
Champigny
Emile
E
Levy
Vincent
V
Giguère
D000818:Animals; D000833:Animals, Suckling; D001054:Apolipoproteins A / Q000235:genetics*; D001483:Base Sequence; D018938:Caco-2 Cells; D004247:DNA / Q000235:genetics; D004734:Energy Metabolism; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
D001054:Apolipoproteins A; D004247:DNA; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C022205:apolipoprotein A-IV