Obese Preeclamptic‐like BPH/5 Female Mice Have Evidence of Hepatic Steatosis with Progression to Non‐Alcoholic Fatty Liver Disease and Steatohepatitis with Pregnancy That Is Partially Reversed by Maternal Weight Loss

Abstract

Maternal obesity before and during early pregnancy has been associated with adverse outcomes, including preeclampsia (PE). Recently, pre‐conception fatty liver in women has been identified as a significant risk factor for the development of PE. Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction with a prevalence of 30% worldwide and 10% in women of childbearing age. To better understand the relationship of maternal obesity and liver function in PE pregnancies, we sought to characterize the hepatic phenotype before and during early pregnancy in the obese preeclamptic‐like BPH/5 mouse. We hypothesized that BPH/5 female mice would have pre‐existing hepatic steatosis that is exacerbated by pregnancy to NAFLD and non‐alcoholic steatohepatitis (NASH), which could be reversed by weight loss to improve pregnancy outcomes.We have previously shown that BPH/5 female mice have an adverse metabolic phenotype in adulthood with obesity, increased pro‐inflammatory white adipose tissue (WAT), and hyperleptinemia as well as dyslipidemia that is exaggerated by pregnancy. To test our hypothesize, BPH/5 females were examined for signs of liver dysfunction before and at early pregnancy, embryonic day (e) 7.5, as well as after calorie restriction beginning at the time of conception, e0.5, by pair‐feeding to age‐ and gestation‐matched ad libitum fed control C57 female mice. This pair‐feeding paradigm has been shown to reduce BPH/5 female body weight significantly compared to ad libitum fed BPH/5 by e3.5 (n=6; p<0.05) and WAT by e10.5 (n=6; p<0.05).BPH/5 female mice have a 25% increase in liver mass before pregnancy versus C57, while their body weight is increased by only 15% (p<0.05, n=3–9). Moreover, non‐pregnant BPH/5 female mice have a trend for increased serum alanine aminotransferase, a circulating hepatic leakage enzyme, versus C57 (45.7±19.5 vs. 30.3±2.3U/L; n=3–4, p=0.1). Hepatic expression of pro‐inflammatory genes, tumor necrosis factor (TNF)α, pan interferon (IFNa), interleukin (IL)‐1β and ‐6, increased by 25, 50, 20, and 100‐fold, respectively with pregnancy at e7.5 as compared to non‐pregnant BPH/5 female livers (n=3–4, p<0.05), but this was not attenuated by pair‐feeding (p>0.05). C57 females do not have increased hepatic expression of TNFα, IFNa, IL‐1 β nor IL‐6 mRNA with pregnancy (n=3–4, p>0.05). Histologic examination of non‐pregnant BPH/5 female livers show excessive hepatic lipid accumulation with microvesicular steatosis. While pregnant (e7.5) C57 livers are free of inflammatory cells and lipid accumulation (n=3), e7.5 BPH/5 livers have an influx of inflammatory cells (1, scale 0–3) along with excess lipid accumulation (1.5, scale 0–3) that is attenuated by pair‐feeding (0.8, n=3). Further investigations are necessary to determine if maternal obesity and liver disease underlie the heightened inflammatory state observed in BPH/5 preeclamptic‐like mice. Furthermore, weight loss in obese BPH/5 may reverse pre‐existing metabolic derangements, including NAFLD to prevent PE associated adverse pregnancy outcomes.