Loss of ER beta in Aging LXR alpha beta Knockout Mice Leads to Colitis

Liver X receptors (LXR alpha and LXR beta) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXR fffi-deficient mice are more susceptible to dextran sodium sulfate (DSS)induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXRff and LXRfi are expressed in the colonic epithelium and that in aging LXR alpha beta (-/-) mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor beta (ER beta) levels. The cytoplasmic compartment of the surface epithelial cells was markedly reduced and there was a massive invasion of macrophages in the lamina propria. The expression and localization of beta-catenin, alpha-catenin, and E-cadherin were not changed, but the shrinkage of the cytoplasm led to an appearance of an increase in staining. In the colonic epithelium there was a reduction in the expression of plectin, a hemidesmosome protein whose loss in mice leads to spontaneous colitis, ELOVL1, a fatty acid elongase protein coding gene whose overexpression is found in colorectal cancer, and non-neuronal choline acetyltransferase (ChAT) involved in the regulation of epithelial cell adhesion. We conclude that in aging LXR alpha beta (-/-) mice, the phenotype in the colon is due to loss of ER beta expression.