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Fatty Acid Translocase (FAT/CD36) Is Localized on Insulin-Containing Granules in Human Pancreatic ß-Cells and Mediates Fatty Acid Effects on Insulin Secretion

¹ Division of Endocrinology & Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California
² Department of Medicine, University of California, Los Angeles, California
³ Research Division, Joslin Diabetes Center, Boston, Massachusetts
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁵ Department of Medicine, Division of Nutrition, Washington University School of Medicine, St. Louis, Missouri

The membrane receptor FAT/CD36 facilitates the major fraction of long-chain fatty acid (FA) uptake by muscle and adipose tissues. In line with the well-known effects of FA metabolism on carbohydrate utilization and insulin responsiveness, altered expression of CD36 has been linked to phenotypic features of the metabolic syndrome including insulin resistance and dyslipidemia. FA metabolism is also known to significantly affect insulin secretion. However, the role of CD36 in this process remains unknown, since its expression levels and function in the pancreas have not been explored. In the present study, freshly isolated human islets and a mouse-derived ß-cell line (MIN6) were shown positive for CD36 expression by RT-PCR, Western blot, and immunofluorescence. The identity of the PCR product was confirmed by microsequencing. The identified transcript was translated and the protein was expressed and subjected to the known posttranslational glycosylation. Fluorescence resonance energy transfer analysis and subcellular protein fractionation indicated that insulin and CD36 are colocalized in the secretory granules of ß-cells. Islet CD36 functioned in FA uptake because this process was blocked by the irreversible CD36 inhibitor sulfosuccinimidyl-oleate. More importantly, sulfosuccinimidyl-oleate reversed enhancing and inhibiting effects, respectively, of acute and long-term palmitate incubations on glucose-dependent insulin secretion. In conclusion, our study demonstrates that human islets express CD36 in the plasma membrane as well as in the insulin secretory granules. CD36 activity appears important for uptake of FA into ß-cells as well as for mediating their modulatory effects on insulin secretion.

Abbreviations: FA, fatty acid; FFA, free FA; FRET, fluorescence resonance energy transfer; IRS, insulin receptor substrate; KRH, Krebs-Ringer-HEPES; SSO, sulfosuccinimidyl-oleate; UTR, untranslated region; VAMP, vesicle-associated membrane protein

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