Lipid-mediated injury plays an important role in the pathogenesis of many renal diseases including diabetic nephropathy. Liver X receptor-␣ (LXR␣) is an intracellular sterol sensor that regulates expression of genes controlling cholesterol absorption, excretion, catabolism, and cellular efflux. The present study was aimed at examining the role of LXR␣ in cholesterol metabolism in glomerular mesangial cells. A 1,561-bp fragment of full-length rabbit LXR cDNA was cloned. The deduced protein

more »

... ce exhibited 92.4 and 89.2% identity to human and mouse LXR␣, respectively. Tissue distribution studies showed that rabbit LXR␣ was expressed in the liver, spleen, and kidney. In situ hybridization and RT-PCR assays further indicated that LXR␣ mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli. To determine intrarenal regulation of LXR␣, rabbits were treated with thiazolidinedione (TZD) peroxisome proliferator-activated receptor-␥ (PPAR␥) agonists, which have been previously shown to enhance LXR␣ expression via PPAR␥ and increase cholesterol efflux in macrophages. The results showed that glomerular LXR␣ expression was markedly induced by TZDs. In cultured rabbit mesangial cells, LXR␣ mRNA and protein were detected by RT-PCR and immunoblotting. Treatment of mesangial cells with a specific LXR␣ agonist, TO-901317, significantly increased basal and apolipoprotein AI-mediated cholesterol efflux and markedly enhanced the promoter activity of an LXR␣ target gene, ATP-binding cassette transporter A1 (ABCA1). In conclusion, LXR␣ is expressed in renal glomeruli and functionally present in mesangial cells where its activation mediates cholesterol efflux via ABCA1. These data suggest that LXR␣ may be a potential therapeutic target for treating lipid-related renal glomerular disease. glomeruli; ATP-binding cassette transporter A1