Cholestatic pregnancy has a gender-specific programming effect in mouse adult offspring
Georgia Papacleovoulou1, Shadi Abu-Hayyeh1, Evanthia Nikolopoulou2, Bryn Owen1, Vanya Nikolova1, Eugene Jansen3, Alex Knisely4 & Catherine Williamson1
Alterations in maternal metabolism can programme disease in the offspring. Intrahepatic cholestasis of pregnancy is a liver disease of pregnancy that presents with increased maternal serum bile acids (BA) and dyslipidaemia. We aimed to investigate whether cholestatic pregnancy affects the subsequent health of the offspring. We developed a cholestatic mouse model by supplementation of a normal chow (NC) diet with 0.5% cholic acid during pregnancy. 18 weeks old female and male offspring fed either a NC or a western diet (WD) for 6 weeks were assessed with several in vivo and in vitro studies. Two cohorts of at least 6 animals/group were tested. Cholestatic pregnancy resulted in mild hepatosteatosis and inflammation in the female adult offspring. This was exacerbated when a WD was fed. WD resulted in an increased BMI, impaired glucose tolerance, insulin resistance, profound hepatosteatosis and increased serum pro-inflammatory (e.g. Tnf-α, Crp and Cd26) and reduced anti-inflammatory (e.g. IL-11) markers. Serum LDL-cholesterol, insulin, leptin and hepatic free fatty acids (FFA) were increased accompanied with increased hepatic triglyceride/FA (Lxrα/Srebp-1c) and reduced cholesterol (Srebp2/Hmgcr) biosynthetic pathways. To dissect underlying mechanisms of this phenotype, we assessed the feto-placental unit of cholestatic mothers. Day 18 fetuses developed a cholestatic phenotype (increased serum BA and induced hepatic Fxr pathways). They also had increased hepatic cholesterol and FA biosynthetic pathways along with increased levels of hepatic FFA and total cholesterol, with no changes in serum levels. Cholestatic placentas had increased lipidic vacuolisation and raised total cholesterol and cholesteryl esters, with increased expression of lipogenic pathways (e.g. Adrp and Acat-2 mRNA) and decreased expression of fatty acid transport pathways (e.g. Fabp-pm and Cd36 mRNA). These data show that cholestatic pregnancy alters placental lipid handling, thereby modifying fetal metabolism and causing increased susceptibility of adult offspring to metabolic disease. This effect is restricted to female offspring. This work was funded by the Genesis Research Trust and the Biomedical Research Centre, Imperial College London.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: Women for Women, Genesis Research Trust.