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.
This work was supported by the Canadian Institutes for Health Research (CIHR). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.