Dietary heme-mediated PPARa activation does not affect the heme-induced epithelial hyperproliferation and hyperplasia in mouse colon

Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARa target genes. The aim of this study was to investigate the role of PPARa in heme-induced hyperproliferation and hyperplasia. Male PPARa KO and WT mice received a purified diet with or without heme. As PPARa is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized that the absence of PPARa leads to more surface injury and crypt hyperproliferation in the colon upon heme-feeding. Heme induced luminal cytotoxicity and lipid peroxidation and colonic hyperproliferation and hyperplasia to the same extent in WT and KO mice. Transcriptome analysis of colonic mucosa confirmed similar heme-induced hyperproliferation in WT and KO mice. Stainings for alkaline phosphatase activity and expression levels of Vanin-1 and Nrf2-targets indicated a compromised antioxidant defense in heme-fed KO mice. Our results suggest that the protective role of PPARa in antioxidant defense involves the Nrf2-inhibitor Fosl1, which is upregulated by heme in PPARa KO mice. We conclude that PPARa plays a protective role in colon against oxidative stress, but PPARa does not mediate heme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of heme-induced hyperproliferation and hyperplasi