Studies on Regulation of the Peroxisomal β-Oxidation at the 3-Ketothiolase Step

Summary

The peroxisomal 3-oxoacyl-CoA thiolase (thiolase) is the last enzyme involved in the β-oxidation of fatty acids. The enzyme cleaves long chain fatty acyl-CoA to generate acetyl-CoA and shortened acyl-CoA. The enzyme is nuclear encoded, synthesized in the cytoplasm and transported into peroxisomes. The thiolase B gene is inducible by the peroxisome proliferator compounds, like other genes involved in β-oxidation of fatty acids in peroxisomes.

The importance of studying thiolase is that it generates acetyl-CoA which is the precursor for the synthesis of molecules like cholesterol and fatty acids. The structural and functional analysis of thiolase at molecular level may add to the knowledge of fatty acid metabolism and further the obesity phenomenon. It is known that several genes mediate lipid homeostasis in target organs like liver, adipose tissue and are regulated by peroxisome proliferator activated receptors (PPARα and PPARγ). To elucidate the mechanism of induction of rat liver thiolase B gene, an upstream 2.8kb fragment containing promoter element has been subcloned and partially sequenced. The sequence analysis revealed a putative PPRE (Peroxisome Proliferator Response Element) of AGACCT T TGAACC sequence at -681 to -668 [Kliever et al. (1992) Nature 358:771–774]. By transient expression of a luciferase reporter gene in HeLa cells, we conclude that the identified Current Views of Fatty Acid Oxidation and Ketogenesis: From Organelles to Point Mutations edited by Quant and Eaton, Kluwer Academic/Plenum Publishers, New York, 1999. PPRE could be functional in induction of thiolase B gene, but other sequences of genes might be involved.