Superfund Research Program
Toxicogenomic Analysis of Nuclear Xenobiotic Receptors
Project Leader: Ronald M. Evans (Salk Institute for Biological Studies)
Grant Number: P42ES010337
Funding Period: 2005-2017
The nuclear hormone receptor RORgamma is a regulator of core circadian and metabolic genes and a key activator for hepatic anti-oxidation and detoxification. To examine how RORgamma mediates response to liver toxins, the research team administered acetaminophen to RORgamma liver-specific KO mice. The pathological mechanisms of hepatic acetaminophen toxicity in these KO mice include compromised mitochondrial function, depletion of endogenous anti-oxidation defenses, and opening of mitochondrial permeability transition pore (MPTP). Initiation of MPTP releases mitochondrial contents such as mitochondria DNA and cytochrome C into the circulation, triggering an innate immune response via activation and recruitment of neutrophils to liver. The combination of MPTP-mediated cell death and overactivation of neutrophils leads to inflammation and hepatic damage in the RORgamma KO mice. This role of RORgamma in mediating cellular bioenergetics and acetaminophen metabolism highlights potential therapeutics for acetaminophen toxicity and liver injury. The research team also identified a surprising role for endurance exercise in protecting against CCl4-induced hepatic damage. Voluntary wheel running reduced the levels of plasma alanine aminotransferase -a classical marker for hepatic damage, and hepatic fibrosis, and partially rescued mitochondrial impairment in CCl4-treated mice. These findings suggest that endurance exercise may protect the liver from CCl4-induced damage, and might also be effective against liver damage induced by other liver toxins. These findings are intriguing and suggest that certain lifestyle choices may be protective against environmental toxicants.