PEX16 absence-associated hepatocyte proliferation is mediated by FXR but suppressed by PPARα.

Abstract

Peroxisomal β-oxidation processes substrate that mitochondria can't handle. For example, C27 bile acid intermediates are subjected to β-oxidation to form C24 bile acids in peroxisomes rather than in mitochondria. Peroxisome proliferation is regulated by peroxisome proliferator-activated receptor α (PPARα), which is mediated by peroxisome membrane protein PEX16. Hepatocyte-specific PEX16-deficient (Pex16^Alb-Cre) mice have an upregulated PPARα signaling and display hepatocyte proliferation. It is unclear how hepatocytes proliferate in Pex16^Alb-Cre mice. In this study, we treated Pex16^Alb-Cre mice with PPARα agonist WY-14,643 and intestinal bile acid sequestrant cholestyramine. In addition to these pharmacological interventions, Pex16^Alb-Cre mice were subjected to abrogation of PPARα and farnesoid X receptor (FXR) by crossing with PPARα-absent mice and FXR-absent mice, respectively. The results showed that WY-14,643 did not further increase hepatocyte proliferation in Pex16^Alb-Cre mice, but PPARα-absent Pex16^Alb-Cre mice (Pparα^-/-/Pex16^Alb-Cre) exhibited increased hepatocyte proliferation. In contrast, FXR-absent Pex16^Alb-Cre mice (FXR^-/-/Pex16^Alb-Cre) displayed reduced hepatocyte proliferation. Bile acids are FXR agonists. Consistently, serum bile acids are elevated in Pex16^Alb-Cre mice, and feeding cholestyramine decreased serum bile acids and inhibited hepatocyte proliferation in Pex16^Alb-Cre mice. These results suggest that hepatocyte proliferation in Pex16^Alb-Cre mice is mediated by FXR but inhibited by PPARα.