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 PPARα target genes. The aim of this study was to investigate the role of PPARα in
heme-induced hyperproliferation and
hyperplasia. Male PPARα KO and WT mice received a purified diet with or without
heme. As PPARα is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized that the absence of PPARα 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 PPARα in
antioxidant defense involves the Nrf2-inhibitor Fosl1, which is upregulated by
heme in PPARα KO mice. We conclude that PPARα plays a protective role in colon against oxidative stress, but PPARα does not mediate
heme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of
heme-induced hyperproliferation and
hyperplasia.