The Effect of PPARs on Fatty Acid Transport Proteins 6531 Membrane Fatty Acid Transport Proteins

In general, PPARa and its concomitant ligands have been implicated in the regulation of many genes involved in hepatic lipid metabolism and energy homeostasis.122,124,131 These include both mitochondrial and peroxisomal P-oxidative enzymes as well as fatty acid synthetase and lipoprotein assembly and transport proteins.124,132 PPARy has been associated primarily with lipolytic effects and is known to regulate enzymes involved in adipocyte differentiation and lipid storage and metabolism, for example, LPL and acyl-CoA synthetase, as well as the hormone leptin.122,124,133

Recent molecular evidence has shown that certain putative membrane fatty acid transport proteins are also modulated in a tissue specific manner via PPARs (Table 6.2). In mice, treatment with the synthetic fibrate WY-14,643 and other PPARa ligands resulted in increased mRNA levels of two of the three major membrane carrier proteins. FAT mRNA levels were increased in both liver and intestinal tissue by treatment with a fibrate,71 whereas FATP mRNA increased primarily in liver only.71,72 The observed increase in both FAT and FATP mRNA in liver was not observed in PPARa-null mice, demonstrating that PPARa was obligatory for the hepatic transcriptional effect.71 FABPpm mRNA levels increased only slightly in liver following treatment with the fibrate and were unaffected by treatment with any other PPARa ligands. Transcription of FAT and FATP mRNA also increased in white adipose tissue of mice and in preadipocyte cell lines by treatment with PPARy ligands, but again transcription of FABPpm was unaffected.71,72 Thus, tissue-specific regulation of FAT and FATP expression has been demonstrated, with hepatic expression of FAT and FATP under the control of PPARa and adipocyte expression under the control of PPARy.71,72 In contrast, it appears that FABPpm expression is not under the control of PPARa or PPARy.

Cloning and sequence analysis of the murine FATP gene identified a putative PPRE in its 5' untranslated region.68 A recent study further characterized

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