UCSF

The liver is a sexually dimorphic and functionally heterogeneous organ. As a result, liver diseases often differ by sex in their severity and susceptibility. Additionally, human liver diseases most often preferentially damage one spatially zonated hepatocyte subpopulation within the liver lobule over another. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one third of the population and is an example of a sexually dimorphic and zonated liver disease, as it has higher prevalence in men and post-menopausal women and preferentially targets pericentral hepatocytes. Sexual dimorphism and lobular zonation are two key biological variables underlying liver physiology and pathophysiology, but not much is currently known about how they relate to each. Understanding the molecular mechanisms that drive liver sexual dimorphism, lobular zonation, and their relationship would provide insight into how these liver diseases manifest and how to better treat them. Through single cell RNA sequencing analysis of wildtype adult mouse livers, we observed that sexual dimorphic gene expression in the liver is restricted to hepatocytes as opposed to any non-parenchymal cell type. We also observed a strong correlation between male and periportal hepatocyte gene expression as well as female and pericentral gene expression. Analysis of predicted upstream regulators revealed that Stat5b, a transcription factor that mediates growth hormone signaling and is known to drive sexually dimorphic gene expression in the liver, is upregulated in male and periportal hepatocytes. We also found that Wnt signaling, which is known to drive zonal hepatocyte gene expression, is upregulated in pericentral and female hepatocytes. Analysis of pre-puberty 1 month mouse livers surprisingly showed that Wnt signaling is less sexually dimorphic, Stat5b signaling is less periportally zonated, and the male periportal and female pericentral pattern is generally weaker. We also deeply characterized actue CCl4 injury in mice, a drug induced liver injury (DILI) that presents as sexually dimorphic and zonated. We found that again sexually dimorphic gene expression is restricted to hepatocytes even post injury and that in female livers there is less pericentral damage as well as faster myeloid driven inflammatory response. Overall, our data shows that the change in systemic signals at puberty, particularly Stat5b, have a direct effect on local zonation signals, especially Wnt signaling, which drives the observed female pericentral and male periportal gene expression pattern in adult mouse hepatocytes. This phenomenon helps explain the observed trend in human liver disease and DILI where they preferentially target one hepatocytes subtype over another and one sex over another.