Characterizing zonated hepatocyte sexual dimorphism and its role in fatty liver disease

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Sex is a strong determinant of susceptibility and severity for many human diseases. Yet it is often ignored as a biological variable. The liver is a sexually dimorphic organ, which leads to significant differences liver disease outcomes between men and women. This includes non- alcoholic fatty liver disease, which affects over 25% of the population. There are currently major gaps in our understanding of what the sex differences are in the liver, the mechanism that drive these differences, and the manifestations of sex differences on liver disease outcome. Besides sex differences, the liver is also known to have significant functional differences along the liver lobule, the basic functional unit of the liver. Liver diseases including NAFLD also show zonation along the lobule in their pathology. To date, little is known about whether sexual dimorphism in the liver is evenly distributed along the liver lobule. We showed that more than half of sexually dimorphic hepatocyte genes show spatial zonation across the liver lobule. Surprisingly these zonated sexual dimorphic genes are asymmetrically distributed across sex and the lobule, which corresponds to zonated sex differences in liver function. We showed that systemic signals that drive sex differences exhibit clear zonated activity while local signals that drive zonation show clear sexually dimorphic activity. Finally, we showed in a liver injury model that shows both zonated damage and sex differences in outcomes that zonated sexual dimorphism in hepatocytes drives the sex differences in the liver’s response to injury. Our hypothesis is that lobular zonation and sexual dimorphism in hepatocytes are coordinately regulated by the interactions between local lobular signals including Wnts and systemic signals including growth hormone. We propose a set of studies to 1) determine the respective roles of local and systemic signals in establishing zonated sexual dimorphism in hepatocytes; 2) characterize how zonated sexual dimorphism in hepatocytes change across different reproductive stages of prepuberty, sexual maturity and menopause; and 3) characterize sex differences in liver response to NAFLD across different reproductive stages. The results of these studies will improve our understanding of how sex differences affect liver disease susceptibility and progression.