Laboratory of Molecular Neuroscience   printer friendly

Genetic regulation and modification of the structure and function of the membrane lipid bilayer
Studies in Stearoyl-CoA desaturase (SCD1, FADS-1) and D6-fatty acid desaturase (FADS-2) deficient mouse models

Metabolism and the systemic role of mono- and unsaturated fatty acids
Genetic analysis and regulation of the structure - function relationship of complex membrane phospholipids. Stearoyl-CoA desaturase (SCD1, FADS-1) and D6-fatty acid desaturase (FADS-2).

The key enzyme, the mitochondrial 3-2-trans enoyl-CoA isomerase (ECI) responsible for the enzymatic transformation of the cis double bond system of polyenoic fatty acids completed our understanding of the degradation of all fatty acids in the ß-oxidation cycle. The rat isomerase has been cloned in this laboratory and the recombinant form of the mouse isomerase crystallized. The eci - null allelic mouse has been generated, which provided new insight and a diagnostic tool in pediatrics to discover a new form of inborn error among the numerous unknown mitochondrial defects in human.

The essential fatty acids linoleic and alpha-linolenic acid are transformed to the eicosa- and docosapolyenoic fatty acid series in a cascade of desaturation and chain elongation reactions, which is initiated by the D6 fatty acid desaturase. We discovered that the chain elongation in this transformation cascade is catalyzed by the microsomal malonyl-CoA dependent fatty acid chain elongation complex. De nova synthesized palmitic and stearic acids are desaturated by stearoyl-CoA desaturase (SCD-1; FAD-1), whereas the essential fatty acids are desaturated by D6-fatty acid desaturase (FADS-2). To get insight into the role of mono- and poly-unsaturated fatty acids as membrane constituents for their biophysical properties and precursor functions of biologically highly active signal molecules, we generated both the scd1-/- and fads2-/- knock out mouse mutants by gene targeting. We discovered the important role of SCD1 in transepidermal water barrier regulation and for temperature and energy homeostasis.

The lack of polyunsaturated fatty acids (PUFAs) in the fads2-/- mouse abolishes the eicosanoid synthesis via the cyclic (cyclooxygenases) and linear lipoxygenase pathways. FADS-2 deficiency disturbs the initial platelet aggregation step in the coagulation system. PUFA deficiency in phospholipids of the membrane lipid bilayer has a strong impact on membrane domain structures, e.g. leads to the disruption of intercellular adherens junction systems of the blood-testis barrier and causes male and female sterility. The complex phenotypic analysis of the auxotrophic fads2-/- mutant is under way


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Figure 1: The key role of D6-desaturase in the metabolism of essential fatty acids


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Figure 2: Induced thromboembolism in carotoid artery of wt (+/+) and fads2-/- mice.


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Figure 3: Histology of wt- and -/- mouse.


References
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  22. W. Stoffel, W. Kahlke The transformation of phytol into 3,7,11,15-tetramethylhexadecanoic (phytanic) acid in Heredopathia atactica polyneuritiformis (Refsum's syndrome) Biochem. Biophys. Res. Comm., 19, 33-36 (1965)
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  24. W. Stoffel, H. Wiese Die Biosynthese der Öl-, Linol- und ?-Linolsäure in Phycomyces blakesleanus Hoppe-Seyler's Zeitschr. Physiol. Chemie, 340, 148-156 (1965)
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  26. W. Stoffel, H. Caesar Der Stoffwechsel der ungesättigten Fettsäuren IV. Zur b-Oxidation der Mono- und Polyenfettsäuren Der Mechanismus der enzymatischen Reaktionen an 2cis-Enoyl-CoA-Verbindungen Hoppe-Seyler's Zeitschr. Physiol. Chemie, 341, 76-83 (1965)
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  28. W. Stoffel, R. Ditzer, H. Caesar Hoppe-Seyler's Zeitschr. Physiol. Chemie, 339, 167-181 (1964)
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  30. W. Stoffel, K. L. Ach Der Stoffwechsel der ungesättigten Fettsäuren. II. Eigenschaften des kettenverlängernden Enzyms. Stoffwechsel von cis-b-g-Enoyl-Coenzym A-Verbindungen Angewandte Chemie, 76, 440-441 (1964)
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  33. W. Stoffel, E. Bierwirth
    Synthese [1-14C]-markierter Polyenfettsäuren
    Angewandte Chemie, 74, 905-906 (1962)


July 12, 2011
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