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

Authors

Xue Chen, Anna Mazur, Krista L Denning, George K Acquaah-Mensah, Thao Thi Nguyen, Wei Xu, Long Wang, Zhongjiao Chen, Maafi R Islam, Wei Li, William Galloway, Jun Fan, James Denvir, Logan Marshall Lawrence, Trudy Atuahene, Subha Arthur, Abdelnaby Khalyfa, Xiaodong Wang, Yongke Lu

Published in

The American journal of pathology. Oct 13, 2026. Epub Oct 13, 2026.

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.

PMID:
42869286
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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