Modeling disorders of fatty acid metabolism in the mouse.

There are at least 17 enzymes involved in mitochondrial fatty acid oxidation encoded by at least 21 genes. For most of these genes, humans with genetic deficiencies have been identified. The mouse possesses a very similar fatty acid oxidation system and has served well as an organism for modeling genetic loss of function. Knockout mice have been created for 12 fatty acid oxidation genes, including all three carnitine palmitoyltransferase-1 genes, four of the acyl-CoA dehydrogenases, both subunits of trifunctional protein, short/medium-chain hydroxyacyl-CoA dehydrogenase, and two enzymes required for oxidation of polyunsaturated fatty acids (enoyl-CoA isomerase and 2,4 dienoyl-CoA reductase). This review covers the knowledge that has been gained from these mouse models in terms of understanding both single-gene fatty acid oxidation disorders and the contribution of the fatty acid oxidation pathway to polygenic diseases such as obesity and type 2 diabetes. Also reviewed are other mouse models displaying phenotypic aspects of a fatty acid oxidation disorder such as knockout mice lacking the carnitine transporter and knockouts of key regulators of the pathway such as peroxisome proliferator-activated receptor-α and sirtuin-3. Finally, nongenetic means of manipulating fatty acid oxidation in the mouse are discussed, in particular the various chemical inhibitors that have been used successfully in vivo.