Regulation of the Aldo-Keto Reductase Gene akr1b7 by the Nuclear Oxysterol Receptor LXRα (Liver X Receptor-α) in the Mouse Intestine: Putative Role of LXRs in Lipid Detoxification Processes

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 18; no. 4; pp. 888 - 898
• Main Authors: Volle, David H, Repa, Joyce J, Mazur, Andrzej, Cummins, Carolyn L, Val, Pierre, Henry-Berger, Joelle, Caira, Francoise, Veyssiere, Georges, Mangelsdorf, David J, Lobaccaro, Jean-Marc A
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01.04.2004; Oxford University Press
• Subjects: Life Sciences
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2003-0338

Liver X receptors (LXRs) regulate the expression of a number of genes involved in cholesterol and lipid metabolism after activation by their cognate oxysterol ligands. AKR1-B7 (aldo-keto reductase 1-B7) is expressed in LXR target tissues such as intestine, and because of its known role in detoxifying lipid peroxides, we investigated whether the AKR1-B7 detoxification pathway was regulated by LXRs. Here we show that synthetic LXR agonists increase the accumulation of AKR1-B7 mRNA and protein levels in mouse intestine in wild-type but not lxr−/− mice. Regulation of akr1b7 by retinoic X receptor/LXR heterodimers is dependent on three response elements in the proximal murine akr1b7 promoter. Two of these cis-acting elements are specific for regulation by the LXRα isoform. In addition, in duodenum of wild-type mice fed a synthetic LXR agonist, we observed an LXR-dependent decrease in lipid peroxidation. Our results demonstrate that akr1b7 is a direct target of LXRs throughout the small intestine, and that LXR activation plays a protective role by decreasing the deleterious effects of lipid peroxides in duodenum. Taken together, these data suggest a new role for LXRs in lipid detoxification.