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E3‐bglobin‐D d mice: A new model to study hepatic zonal regulation of sex‐biased cytochrome p450 mRNA expression
Author(s) -
Nail Alex N.,
Jiang Jieyun,
Peterson Martha L.,
Spear Brett T.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.920.8
Subject(s) - cytochrome p450 , biology , gene , hepatocyte , hepatocellular carcinoma , enhancer , gene expression , drug metabolism , cancer research , genetics , enzyme , biochemistry , in vitro
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is the third leading cause of cancer death overall. In addition, HCC rates are much higher in males than in females. Our lab primarily focuses on liver genetic regulation and how dysregulated genes contribute to liver development and disease, including HCC. The cytochrome p450 (Cyp) family of enzymes are expressed mainly in the liver and have a critical role in the metabolism and biotransformation of endogenous and xenobiotic compounds. Many Cyps are expressed zonally in the livers of both mice and humans and, in addition, have been found to exhibit sex‐biased expression. Our lab has developed a novel model to study zonal hepatocyte populations within the liver. We have placed the H‐2D d reporter gene under control of pericentrally active alpha‐fetoprotein E3 enhancer. Using antibodies against the D d protein, which is expressed on the cell surface, we can separate pericentral and periportal hepatocytes using flow cytometry. This system enables us to analyze previously identified and novel zonally regulated genes. Using this system, we have identified Cyps that are both sex‐biased and zonally restricted within the mouse liver. Interestingly, the highly related Cyp2a4 and Cyp2a5 are female‐biased genes expressed periportally and pericentrally, respectively. These two genes have 97% genomic sequence identity over a 30 Kb region, providing a model to study sex‐biased and zonal regulation in the liver. Our central hypothesis is that sex‐biased zonally regulated Cyp enzymes contribute to sex‐biased HCC development. Understanding the roles of sex‐biased pericentral and periportal genes may lead to new insights into the basis for HCC predominance in males.