Phosphodiesterase 3 B is localized in caveolae and smooth ER in mouse hepatocytes and is important in the regulation of glucose and lipid metabolism

Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor c, sterol regulatory elementbinding protein 1c and hydroxyl-3-methylglutaryl coenzyme A reductase. In conclusion, hepatocyte PDE3B is localized in caveolae and smooth endoplasmic reticulum and plays important roles in the regulation of glucose, triglyceride and cholesterol metabolism. Dysregulation of PDE3B could have a role in the development of fatty liver, a condition highly relevant in the context of type 2 diabetes. Citation: Berger K, Lindh R, Wierup N, Zmuda-Trzebiatowska E, Lindqvist A, et al. (2009) Phosphodiesterase 3B Is Localized in Caveolae and Smooth ER in Mouse Hepatocytes and Is Important in the Regulation of Glucose and Lipid Metabolism. PLoS ONE 4(3): e4671. doi:10.1371/journal.pone.0004671 Editor: Silvana Gaetani, Sapienza University of Rome, Italy Received November 14, 2008; Accepted January 28, 2009; Published March 5, 2009 Copyright: 2009 Berger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Swedish Research Council Project 3362 to E.D; K.B. was supported by Lund University Diabetes Center (LUDC); Grants were obtained from the following foundations: Swedish Diabetes Association; Novo Nordisk, Denmark; The Swedish Society of Medicine, Dr. P. Hakansson, Albert Pahlsson, Fredrik och Ingrid Thuring, Wiberg, Lars Hierta, Ahlà n, Tore Nilsson and Magn. Bergvall. The funding agencies did not take any part in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: karin.berger@med.lu.se . These authors contributed equally to this work.