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Mouse Models of Liver Disease Highlight Important Roles of Temperature and Sex

Recent studies with animal models of two different forms of liver disease demonstrate the importance of factors such as the sex of the animals and even the ambient temperature where they are housed in designing experiments that are relevant to human disease.

Nonalcoholic fatty liver disease (NAFLD) is a form of chronic liver disease in both women and men; it is associated with obesity and other metabolic disorders and is on the rise in the United States and around the world. In NAFLD, fat builds up in the liver, sometimes followed by more severe disease marked by liver inflammation and scarring that can lead to cirrhosis, liver failure, and liver cancer. But, despite its prevalence and potential severity, treatments for NAFLD are limited. Few animal models exist to study NAFLD, with the most prominent being a mouse model fed a high-fat diet to elicit NAFLD-like disease. These mice, however, show marked differences from their human counterparts with NAFLD, namely that the mice have less liver inflammation and scarring, and also the female mice show no signs of NAFLD and therefore cannot be studied with this model. Researchers sought to improve the relevance of this animal model of NAFLD to humans by optimizing the environment of the mice and thereby altering their physiology. The researchers noted that mice in the laboratory are typically housed at temperatures adjusted for human comfort, but mouse metabolism functions more efficiently at warmer temperatures. With this in mind, the researchers raised the temperature of the room where the mice on the high-fat diet were housed to align more closely with mouse metabolism. They found that this simple change resulted in altered responses in the mice, most notably a more pronounced NAFLD-like disease, even in the female mice. A myriad of physiological changes were also apparent with the thermostat adjustment, compared to the usual temperature set for human comfort, including heightened inflammatory responses, greater intestinal permeability, and alterations in the gut microbes—all of which are features of human NAFLD. This study shows how changing the temperature under which mice are typically housed improves the utility of a mouse model for studying human liver disease, particularly in females. This finding could enable future studies to better understand disease processes underlying NAFLD as a foundation for developing improved therapeutic approaches.

In another type of liver disease, called primary sclerosing cholangitis (PSC), the ducts that drain the bile from the liver are damaged, with inflammation leading to scarring and blockage of the ducts over time and a back-up of bile into the liver. Liver cirrhosis and liver failure can result, requiring transplantation. Both men and women are susceptible to PSC, though the disease is more common in men. Animal models of this disease aid in the understanding of disease processes and in developing new approaches to treatment. One research group investigated a genetically modified mouse model that spontaneously develops features of PSC due to the absence of a key component of bile. Interestingly, the mice also display an unusual sex difference—the female mice develop more severe liver injury than the males. The researchers probed this model to uncover mechanisms underlying the disease, particularly in females compared to males. They identified the molecular pathways associated with the different stages of disease in the female mice compared to males. In particular, they noted that female mice had dramatically higher levels of a molecule called H19 produced in the bile duct cells that regulates cell proliferation and differentiation into specific cell types. By reducing the levels of H19, the group was able to reduce liver injury in the female mice. In human samples from people with PSC, the researchers showed the same alterations in molecules such as H19 as in the PSC mouse model. These results highlight clinically relevant molecular factors involved in PSC that may also play a role in sex-related differences in disease progression. Factors such as H19 may represent a new target for the development of future therapies against diseases such as PSC.

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