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Autonomous Province Bolzano / South Tyrol Project

Role of Alkylglycerol Monoxygenase and Tetrahydrobiopterin Biosynthesis in Adipocyte Function

Project leader:
Assoc.Prof. Priv.-Doz. Mag. Katrin Watschinger, PhD
Institute of Biological Chemistry, Biocenter
Medical University of Innsbruck

Approved: 11.10.2012
Grants awarded: 258,770.00 €
Project start: 01.02.2013
Project end: 31.07.2016
Science discipline: Medical Biochemistry (100%)

Abstract:

Modern life style in Western countries leads to an alarming increase in body weight and pathologies related to obesity. 20 year follow-up data from a Caucasian population of the small town Bruneck in South Tyrol have shown that about 1% of all tested persons between 40 and 79 years developed type 2 diabetes every year. Therefore, novel therapeutic targets to interfere with fat storage and related pathologies are desperately needed.

Besides the well described major fat storage lipids, the triacylglycerides, there are other glycerol-linked lipid species which may represent a novel strategy to control and reduce body fat. These alkylglycerols have long aliphatic side chains which are linked via an ether-bond to the glycerol backbone. A single enzyme has been described which is capable of cleaving such ether-linked chains, alkylglycerol monooxygenase [EC 1.14.16.5].

Alkylglycerol monooxygenase belongs to the family of tetrahydrobiopterin-dependent enzymes. We have recently succeeded in identifying the gene coding for this enzyme and we now want to investigate expression and enzymatic activity during differentiation of SGBS cells, an adipocyte cell line, and primary human adipocytes. We also want to study the biosynthesis of tetrahydrobiopterin in SGBS cells by measuring both activity and expression of the catalytic triad GTP-cyclohydrolase, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. In a next step, we want to modulate alkylglycerol monooxygenase and GTP-cyclohydrolase expression and activity by different stimuli and overexpression or knockdown, and document the impact on adipocyte function and differentiation. As alkylglycerol monooxygenase is the only enzyme capable of cleaving ether-lipids it can be assumed that activity up- and downregulation is reflected in the cellular lipid composition. For this we will generate cellular lipid profiles from conditions of strong alkylglycerol monooxygenase activity modulation. These experiments will be completed by gene array analyses which will allow us to identify genes or gene clusters with similar regulation and potentially similar implications in adipocyte function.

This project aims to give insights into the role of alkylglycerol monooxygenase and tetrahydrobiopterin in differentiation and function of adipocytes. In our current situation of dramatically increasing pathologies related to excessive weight gain, it is of great importance to identify novel players involved in the physiology of adipose tissue which can become promising targets in our efforts against obesity and type 2 diabetes in the future.