University of Texas Southwestern Medical Center

About: University of Texas Southwestern Medical Center is a healthcare organization based out in Dallas, Texas, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 39107 authors who have published 75242 publications receiving 4497256 citations. The organization is also known as: UT Southwestern & UT Southwestern Medical School.

Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta.

Abstract: LXRα and -β are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. Previously, we have proposed that LXRs regulate these pathways through their interaction with specific, naturally occurring oxysterols, including 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol. Using a ligand binding assay that incorporates scintillation proximity technology to circumvent many of the problems associated with assaying extremely hydrophobic ligands, we now demonstrate that these oxysterols bind directly to LXRs at concentrations that occur in vivo. To characterize further the structural determinants required for potent LXR ligands, we synthesized and tested a series of related compounds for binding to LXRs and activation of transcription. These studies revealed that position-specific monooxidation of the sterol side chain is requisite for LXR high-affinity binding and activation. Enhanced binding and activation can also be achieved through the use of 24-oxo ligands that act as hydrogen bond acceptors in the side chain. In addition, introduction of an oxygen on the sterol B-ring results in a ligand with LXRα-subtype selectivity. These results support the hypothesis that naturally occurring oxysterols are physiological ligands for LXRs and show that a rational, structure-based approach can be used to design potent LXR ligands for pharmacologic use.

Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.

Abstract: The intestinal epithelium is in direct contact with a vast microbiota, yet little is known about how epithelial cells defend the host against the heavy bacterial load To address this question we studied Paneth cells, a key small intestinal epithelial lineage We found that Paneth cells directly sense enteric bacteria through cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors Paneth cells were essential for controlling intestinal barrier penetration by commensal and pathogenic bacteria Furthermore, Paneth cell-intrinsic MyD88 signaling limited bacterial penetration of host tissues, revealing a role for epithelial MyD88 in maintaining intestinal homeostasis Our findings establish that gut epithelia actively sense enteric bacteria and play an essential role in maintaining host-microbial homeostasis at the mucosal interface