PPARα agonist fenofibrate attenuates iron-induced liver injury in mice by modulating the Sirt3 and β-catenin signaling

Ashok Mandala, William J. Chen, Austin Armstrong, Milan R. Malhotra, Sanmathi Chavalmane, Kyle S. McCommis, Anping Chen, Danielle Carpenter, Pratim Biswas, Jaya P. Gnana-Prakasam

Research output: Contribution to journalArticlepeer-review

Abstract

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/β-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator-activated receptor α (PPARα) agonist, fenofibrate, prevents iron-induced oxidative stress and β-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD+-dependent deacetylase, that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury (IRI) by normalizing the Wnt/β-catenin pathway. In the present study, we explored if fenofibrate prevents iron-induced liver injury by regulating the Sirt3 and β-catenin signaling. In vitro and in vivo iron treatment resulted in the downregulation of PPARα, Sirt3, active β-catenin, and its downstream target gene c-Myc in the mouse liver. Pharmacological activation of Sirt3, both in vitro and in vivo, by Honokiol (HK), a known activator of Sirt3, abrogated the inhibitory effect of iron overload on active β-catenin expression and prevented the iron-induced upregulation of a smooth muscle actin (αSMA) and TGFβ expression. Intrinsically, PPARα knockout mice showed significant downregulation of hepatic Sirt3 levels. In addition, treatment of iron overload mice with PPARα agonist fenofibrate reduced hepatic iron accumulation and prevented iron-induced downregulation of liver Sirt3 and active β-catenin, mitigating the progression of fibrosis. Thus, our results establish a novel link between hepatic iron and PPARα, Sirt3, and β-catenin signaling. Further exploration on the mechanisms by which fenofibrate ameliorates iron-induced liver injury likely has significant therapeutic impact on iron-associated chronic liver diseases.

Original languageEnglish (US)
Pages (from-to)G262-G269
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume321
Issue number3
DOIs
StatePublished - Sep 2021

Keywords

  • Fenofibrate
  • Iron
  • Liver
  • Sirt3
  • β-catenin

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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