Coagulopathy in Malnourished Mice is Sexually Dimorphic and Regulated by Nutrient-sensing Nuclear Receptors

Liver dysfunction including coagulopathy is a prominent feature of proteinenergy malnutrition. To identify mechanisms underlying malnutrition-associated coagulopathy, we administered low-protein low-fat diet to lactating dams and examined hepatic transcription and plasma coagulation parameters in young adult weanlings. Malnutrition impairs growth and liver synthetic function more severely in males versus females. Malnourished males are coagulopathic and exhibit decreased hepatocyte peroxisomes, FXR agonist bile acids, FXR binding on Fga and F11 gene regulatory elements, and coagulation factor synthesis. These effects are absent in female mice, which have low baseline levels of PPARα, suggesting that nutrient-sensing nuclear receptors regulate coagulation factor synthesis in response to host nutritional status in a sex-specific manner. Wild type C57BL/6J mice (Jackson Laboratory) were maintained in the Baylor College of Medicine Center for Comparative Medicine in a temperature-controlled 14:10 hour light:dark room. Dams with 8-day-old pups were randomized to receive irradiated purified control diet (15% fat, 20% protein, 65% carbohydrate) or isocaloric LPLFD (5% fat, 7% protein, 88% carbohydrate) to induce malnutrition. On day-of-life 21, pups were weaned to their dams’ diet for another 5 weeks. At 8 weeks of life, mice were lightly anesthetized with isoflurane. After euthanization by 2 minutes of CO2 inhalation, plasma was collected by cardiac puncture into syringes pre-filled with 0.9% sodium citrate. Liver lobes then were harvested.