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Identification of a Liver-Specific Uridine Phosphorylase that Is Regulated by Multiple Lipid-Sensing Nuclear Receptors

Department of Pharmacology and Howard Hughes Medical Institute (Y.Z., D.J.M.), University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050; Departments of Physiology and Internal Medicine (J.J.R.), Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8854; and Laboratory of Metabolism (Y.I., G.P.H., F.J.G.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: David J. Mangelsdorf, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9050. E-mail: Davo.Mango{at}utsouthwestern.edu.

In this work, we report the characterization of a novel liver-specific gene (L-UrdPase), whose expression is regulated by a number of hepatic nuclear receptors (including liver X receptors, peroxisome proliferator-activated receptor , farnesoid X receptor, and hepatic nuclear factor-4), which have been shown to be involved in lipid metabolism. L-UrdPase encodes a previously uncharacterized protein with similarity to an intestine-specific uridine phosphorylase. Enzymatic assays confirmed that L-UrdPase has uridine phosphorylase activity. However, L-UrdPase has a highly restricted, nonoverlapping pattern of expression with its intestinal counterpart and is regulated in a distinct manner by several different nuclear receptors. The identification of the liver uridine phosphorylase and its characterization as a target of lipid-sensing nuclear receptors implies the existence of a previously unknown nuclear receptor signaling pathway that links lipid and uridine metabolism.

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  PPARα  |  LXRβ  |  LXRα  |  FXRα  |  PXR  |  HNF4α

Ligands:   Pregnenolone carbonitrile  |  LGD 100268  |  T0901317