Peroxisome Proliferator Activated Receptor-a Expression in Human Liver

The peroxisome proliferator activated receptor a (PPAR) is a member of the steroid/hormone receptor superfamily that mediates the peroxisome proliferator-dependent transcriptional activation of genes encoding several peroxisomal and microsomal enzymes as well as peroxisome proliferation. Human liver is refractory to the pathological effects of peroxisome proliferators that are seen in mice. With the use of RNase protection assays, the ratio of hepatic PPARa mRNA to b-actin mRNA was found to be 1 order of magnitude lower in humans than that observed in mice. In addition, the isolation of human cDNA for PPARa that does not encode a functional PPAR because it lacks exon 6 as a result of alternate RNA splicing suggested that this process might also diminish the expression of PPARa. RNase protection analysis of total RNA revealed the presence of splice variants lacking exon 6 at significant levels in all 10 human liver samples examined. Supershift analysis using the CYP4A6-Z peroxisome proliferator response element and antisera specific for PPARa revealed easily detectable amounts of PPARa DNA binding activity in mouse liver lysates, whereas human liver lysates contained .10-fold lower amounts of PPARa DNA binding activity. In contrast to mouse lysates, the amount of PPARa binding in human lysates was generally less than that of other unidentified proteins. These results suggest that although humans retain the coding potential for a functional receptor, the low levels of PPARa expression in liver may be insufficient to compete effectively with other proteins that bind to peroxisome proliferator response elements. A wide range of chemicals that cause an increase in the size and number of peroxisomes and ultimately lead to hepatocarcinogenesis in rodents are collectively known as peroxisome proliferators (Moody et al., 1991; Rao and Reddy, 1987). The increase in peroxisome size and number is accompanied by increases in peroxisomal fatty acid b-oxidation and microsomal v-hydroxylation (Sharma et al., 1988). It has been proposed that the increased levels of H2O2 produced by increased peroxisomal b-oxidation leads to DNA damage and tumor formation (Reddy and Rao, 1989). Moreover, peroxisome proliferators elicit hepatomegaly and hyperplasia, which could contribute to tumorigenesis (Moody et al., 1991; Rao and Reddy, 1987). These pathological processes are evident in mouse and rat liver but have not been observed to any significant extent in primates (Lock et al., 1989). Furthermore, unlike in rodent hepatocytes, exposure to peroxisome proliferators did not have any significant effect on the peroxisomal b-oxidation in primary cultures of human hepatocytes (Bichet et al., 1990; Blaauboer et al., 1990; Elcombe and