Impact of Maternal Obesity on Offspring Bile Acid Homeostasis and Pathologic Progression in Non‐Alcoholic Fatty Liver Disease
Authors: Thompson Michael David , Derse Alaina , Ferey Jeremie LA , Reid Michaela , Xie Yan , Christ Miranda , Chatterjee Deyali , Moley Kelle H , Davidson Nicholas O 
Published: June 2021

Background

Non‐alcoholic fatty liver disease (NAFLD) affects approximately one‐quarter of the global population, with up to 20–25% developing progressive liver disease. Recent evidence in both humans and animal models show that maternal obesity is a risk factor for the development of NAFLD and progression to NASH. We have shown in a murine model of maternal obesity the offspring develop periportal fibrosis and inflammation with associated changes in bile acid (BA) homeostasis. In this study we further define the changes in BA homeostasis and evaluate disease progression in offspring exposed to a western diet.

Methods

Female C57Bl6 mice were fed chow (CON) or HF/HS diet for 6 weeks to induce obesity and bred with lean males. Subsequent mating of F1 and F2 female offspring to lean males was done to develop the F2 and F3 generations, respectively. Offspring were fed chow or high trans‐fat, cholesterol, fructose (HTFC) diet for 16 weeks to induce progressive NAFLD. Metabolic and histopathologic analyses were performed.

Results

In chow fed F1 offspring from the maternal HF/HS (mHF/HS) lineage, total BA pool size was increased and intrahepatic BA composition was shifted with associated changes in expression of genes involved in bile acid metabolism (increased Cyp7a1, Cyp27a1). In F1 offspring fed HTFC, BA pool size increased in mCON lineage and paradoxically decreased in mHF/HS lineage. Measurement of specific bile acids in liver showed a shift in the intrahepatic BA pool composition (decreased FXR agonists, increased FXR antagonists) in offspring from the mHF/HS lineage. No difference in BA pool size was observed in the F2 and F3 generation offspring. F1 offspring from the mHF/HS showed increased steatosis and intrahepatic triglyceride. No difference in steatosis occurred in the F2 and F3 generations. Conversely, inflammation and fibrosis were decreased in F1 offspring from the mHF/HS lineage compared to mCON. F2 and F3 offspring from the mHF/HS lineage also exhibited less fibrosis.

Conclusions

Maternal HF/HS diet exposure leads to pathologic changes in the offspring including periportal fibrosis and inflammation. However, during western diet feeding F1 offspring of obese dams exhibit worse steatosis but less inflammation and fibrosis. There are associated changes in BA homeostasis, but a causal link is not clear. Future work will focus on defining the mechanism of changes in BA homeostasis and whether these changes are causally related to the observed phenotype.

Support or Funding Information

Child Health Research Center at Washington University School of Medicine K12‐HD076224 (MDT), DDRCC DK‐52574 (MDT, NOD), Washington University ICTS JIT Award (MDT), DK‐56260 (NOD), HL‐38180 (NOD), HL‐140848 (JLAF), HD‐83895 (KHM).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.