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J. Biol. Chem., Vol. 279, Issue 5, 3828-3836, January 30, 2004

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A Novel Hormone-sensitive Lipase Isoform Expressed in Pancreatic -Cells^*

Håkan Lindvall, Pernilla Nevsten¶, Kristoffer Ström, Reine Wallenberg¶, Frank Sundler||, Dominique Langin**, Maria Sörhede Winzell, and Cecilia Holm

From the Department of Cell and Molecular Biology, the ^¶National Center for High Resolution Electron Microscopy, the ^||Department of Physiological Sciences, and the Department of Medicine, Lund University, SE-22184 Lund, Sweden, and the ^**Unité de Recherches sur les Obésités, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 586, Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, 31403 Toulouse, France

Hormone-sensitive lipase (HSL) is a key enzyme in fatty acid mobilization in many cell types. Two isoforms of HSL are known to date, namely HSL_adi (84 kDa in rat) and HSL_tes (130 kDa in rat). These are encoded by the same gene, with exons 1-9 encoding the parts that are common to both and an additional 5'-exon encoding the additional amino acids in HSL_tes. HSL of various tissues, among these the islet of Langerhans, is larger than HSL_adi, but not as large as HSL_tes, indicating that there may be other 5'-coding exons. Here we describe the molecular basis for a novel 89-kDa HSL isoform that is expressed in -cells, adipocytes, adrenal glands, and ovaries in the rat and that is encoded by exons 1-9 and exon A, which is spliced to exon 1 and thereby introducing an upstream start codon. The additional 5'-base pairs encode a 43-amino acid peptide, which is highly positively charged. Conglomerates of HSL molecules are in close association with the secretory granules of the -cell, as determined by immunoelectron microscopy with antibodies targeting two separate regions of HSL. We have also determined that the human genomic sequence upstream of exon A has promoter activity in INS-1 cells as well as glucose sensing capability, mediating an increase in expression at high glucose concentration. The minimal promoter is present within 170 bp from the transcriptional start site and maximal glucose responsiveness is conferred by sequence within 850 bp from the transcriptional start site.

Received for publication, October 16, 2003

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY428844.

^* This work was supported by the Swedish Research Council (to C. H. and R. W.), a Center of Excellence grant from the Juvenile Diabetes Foundation, USA, the Knut and Alice Wallenberg Foundation, Sweden, the Swedish Diabetes Association, and the Novo Nordisk, Swedish Nutrition, and A. Påhlsson Foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, Section for Molecular Signaling, Lund University, Biomedical Center (BMC), C11, SE-22184 Lund, Sweden. E-mail: hakan.lindvall{at}medkem.lu.se.

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