The general importance of DNL is emphasized by the finding that the generation of homozygous knock-out mice lacking important enzymes of DNL - such as CL (Beigneux et al. 2004), ACC 1 (Abu-Elheiga et al. 2005) and also FAS (Chirala et al. 2003) - is impossible because these mice have lethal development defects, suggesting an important role for DNL in embryonic development (Beigneux et al. 2004).
As already mentioned, one important step of DNL is the carboxylation of acetyl-CoA to form malonyl-CoA that is catalyzed by ACC (Fig. 1.1). Malonyl-CoA is an important metabolic intermediate that signals to the cell that surplus energy is available (Ruderman et al. 2003). Furthermore, besides being an intermediate in DNL, malonyl-CoA also plays a pivotal role in the control of fatty acid oxidation (Abu-Elheiga et al. 2000). Two isoforms of ACC (ACC 1 and ACC 2) have been identified in animals and humans. ACC 1 is a cytosolic protein that is highly expressed in lipo-genic tissues, such as liver and adipose tissue. ACC 2 is associated with mitochondria suggesting that it is mainly involved in the control of mito-chondrial fatty acid oxidation. In line with this assumption, ACC 2 is expressed in tissues such as muscle and brain, in which little or no DNL takes place (Abu-Elheiga et al. 2000). Whereas the genetic lack of ACC 1 is lethal (Abu-Elheiga et al. 2005), mice lacking ACC 2 have a normal life span, a higher fatty acid oxidation rate and less adipose tissue weight (Abu-Elheiga et al. 2001). Furthermore, ACC 2-deficient mice turned out to be protected against obesity and diabetes induced by a high-fat, high-carbohydrate diet (Abu-Elheiga et al. 2003). Therefore, ACC 2 seems to be an interesting therapeutic target in the fight against obesity and related disorders.
All these findings support the important role of DNL in energy homeo-stasis, but also in embryonic development. With respect to the latter aspect it is very important to consider possible teratogenic consequences of anti-obesity drugs aimed at inhibiting DNL.
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