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GPR39 Splice Variants Versus Antisense Gene LYPD1: Expression and Regulation in Gastrointestinal Tract, Endocrine Pancreas, Liver, and White Adipose Tissue

Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology (K.L.E., B.H., P.S.P., T.W.S.) and Department of Biomedical Sciences (J.B.H.), University of Copenhagen, DK-2200 Copenhagen N, Denmark; Department of Neuroscience (J.M., T.H.), Karolinska Institutet, 171 77 Stockholm, Sweden; and 7TM Pharma A/S (T.W.S.), DK-2790 Hoersholm, Denmark

Address all correspondence and requests for reprints to: Thue W. Schwartz, Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. E-mail: schwartz{at}molpharm.dk.

G protein-coupled receptor 39 (GPR39) is a constitutively active, orphan member of the ghrelin receptor family that is activated by zinc ions. GPR39 is here described to be expressed in a full-length, biologically active seven-transmembrane form, GPR39-1a, as well as in a truncated splice variant five-transmembrane form, GPR39-1b. The 3' exon of the GPR39 gene overlaps with an antisense gene called LYPD1 (Ly-6/PLAUR domain containing 1). Quantitative RT-PCR analysis demonstrated that GPR39-1a is expressed selectively throughout the gastrointestinal tract, including the liver and pancreas as well as in the kidney and adipose tissue, whereas the truncated GPR39-1b form has a more broad expression pattern, including the central nervous system but with highest expression in the stomach and small intestine. In contrast, the LYPD1 antisense gene is highly expressed throughout the central nervous system as characterized with both quantitative RT-PCR and in situ hybridization analysis. A functional analysis of the GPR39 promoter region identified sites for the hepatocyte nuclear factors 1 and 4 (HNF-1 and -4) and specificity protein 1 (SP1) transcription factors as being important for the expression of GPR39. In vivo experiments in rats demonstrated that GPR39 is up-regulated in adipose tissue during fasting and in response to streptozotocin treatment, although its expression is kept constant in the liver from the same animals. GPR39-1a was expressed in white but not brown adipose tissue and was down-regulated during adipocyte differentiation of fibroblasts. It is concluded that the transcriptional control mechanism, the tissue expression pattern, and in vivo response to physiological stimuli all indicate that the GPR39 receptor very likely is of importance for the function of a number of metabolic organs, including the liver, gastrointestinal tract, pancreas, and adipose tissue.

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