The Role of the Ah Receptor in Liver Cell Death

Kristen A. Mitchell, Ph.D. and Cornelis Elferink, Ph.D.
University of Texas Medical Branch
F32ES013588, R01ES007800, T32ES007254, and P30ES006676

Background: Apoptosis, or programmed cell death, is rare in healthy adult livers, but certain disease states such as liver cirrhosis and viral hepatitis show marked increases in liver cell apoptosis. This event is signaled through a protein on the surface of cells known as the Fas death receptor. Activation of the receptor triggers a cascade of events that lead to cell death. The aryl hydrocarbon (Ah) receptor, another cellular protein, is known to influence apoptosis presumably by regulating the expression of genes involved in apoptotic signaling. The Ah receptor was discovered in the mid-1970’s and historically, Ah receptor studies focused on the mechanism whereby pollutants, most notably the dioxins and polychlorinated biphenyls, cause a range of adaptive and toxic endpoints. These endpoints appear to reflect disruptions in normal cell growth, apoptosis and cell differentiation. The implication is that the Ah receptor participates in signaling events aimed at maintaining a balance between cell growth and apoptosis. This function is central to normal development and protection from cancer. This research study provides evidence that Ah receptor expression and function cause liver cell death in response to Fas stimulation.

Advance: These researchers used a liver cancer cell line missing the Ah receptor. By reintroducing the receptor into the cells, they found that apoptosis increased dramatically upon stimulation of the Fas receptor. The same was true of cells from the livers of Ah receptor knockout mice­mice genetically manipulated so that they cannot produce the Ah receptor. Additional studies in live mice were conducted that supported the earlier findings. Unlike wild-type mice Ah knockout mice were protected from the lethal effects of an anti­Fas antibody. Using RNA interference to suppress Ah receptor activity by down-regulating the aryl hydrocarbon nuclear translocator partially protected the wild-type mice from the lethal effects of the Fas antibody.

Implications: These experiments consistently demonstrate that Ah receptor is associated with increased susceptibility to Fas-mediated apoptosis. These studies add to the body of knowledge of the innate function of the Ah receptor and the mechanisms by which programmed cell death in the liver occurs.

Citation: Park KT, Mitchell KA, Huang G, Elferink CJ. The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. Mol Pharmacol. 2005 Mar;67(3):612-22.