Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in offspring. Here we evaluated potential mechanisms underlying these phenotypes. Female C57Bl6 mice were fed chow or an obesogenic high-fat/high-sucrose (HF/HS) diet with subsequent mating of F1 and F2 female offspring to lean males to develop F2 and F3 generations, respectively. Offspring were fed chow or fibrogenic (high transfat, cholesterol, fructose) diets, and histopathological, metabolic changes, and bile acid (BA) homeostasis was evaluated. Chow-fed F1 offspring from maternal HF/HS lineages (HF/HS) developed periportal fibrosis and inflammation with aging, without differences in hepatic steatosis but increased BA pool size and shifts in BA composition. F1, but not F2 or F3, offspring from HF/HS showed increased steatosis on a fibrogenic diet, yet inflammation and fibrosis were paradoxically decreased in F1 offspring, a trend continued in F2 and F3 offspring. HF/HS feeding leads to increased periportal fibrosis and inflammation in chow-fed offspring without increased hepatic steatosis. By contrast, fibrogenic diet-fed F1 offspring from HF/HS dams exhibited worse hepatic steatosis but decreased inflammation and fibrosis. These findings highlight complex adaptations in NAFLD phenotypes with maternal diet.
BackgroundNon‐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.MethodsFemale 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.ResultsIn 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.ConclusionsMaternal 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 InformationChild 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.
Background Non‐alcoholic fatty liver disease (NAFLD) affects approximately one‐quarter of the global population with increasing prevalence in the pediatric population. There is currently no standard medical therapy and no diagnostic study capable of predicting which patients will develop severe 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 define the mechanisms of changes in BA homeostasis. Methods Female C57Bl6 mice were fed chow (CON) or HF/HS diet for 6 weeks to induce obesity and bred with lean males. Offspring were fed chow diet from the time of weaning until tissue collection. BA pool size and levels of specific intrahepatic bile acid species were measured. RT‐PCR was performed to evaluate gene expression of factors involved in bile acid metabolism and signaling. 16S sequencing was performed for evaluation of offspring microbiome. Levels of stool BAs were quantified and timed BA excretion performed. Results Offspring from the maternal HF/HS (mHF/HS) lineage exhibited an increase in total BA pool size with associated changes in expression of genes involved in bile acid metabolism (increased Cyp7a1, Cyp27a1). Measurement of specific bile acids in liver showed a shift in the intrahepatic BA pool composition (decreased deoxycholic acid, increased muricholic acid) in offspring from the mHF/HS lineage. Decreased BA excretion was observed in mHF/HS lineage offspring. Fecal microbiome analysis showed a decrease in alpha diversity and shifts in the abundance of particular phyla (increased Bacteroidetes, decreased Proteobacteria) and genera (increased Barnesiella, decreased Clostridium). Measurement of cecal BA levels showed an increase in abundance of muricholic acid (FXR antagonist) and a decrease in abundance of deoxycholic acid (FXR agonist) in mHF/HS lineage offspring. Conclusions Maternal HF/HS diet exposure leads to pathologic changes in the offspring including periportal fibrosis and inflammation, which is associated with changes in BA homeostasis. Several factors are involved in the BA homeostasis changes including BA metabolism and excretion. Vertical transmission of gut dysbiosis may be a primary factor in driving changes in BA homeostasis in offspring exposed to maternal obesogenic diet.
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 altered bile acid homeostasis and a varied response to a western diet which is passed by female offspring across generations. In this study we tested the hypothesis that male offspring exposed to maternal obesogenic diet pass an altered bile acid homeostasis phenotype and susceptibility to western diet induced liver disease to their offspring. Methods Female C57Bl6 mice were fed chow (CON) or HF/HS diet for 6 weeks to induce obesity and bred with lean males. Male F1 offspring were then bred with lean females to create a paternal second generation (PF2C from maternal CON lineage, PF2H from maternal HF/HS lineage). Tissues were collected from PF2 offspring to measure bile acid pool size and hepatic bile acid species profile. Additional PF2 offspring were fed high trans‐fat, cholesterol, fructose (HTFC) diet for 16 weeks to induce progressive NAFLD. Metabolic and histopathologic analyses were performed. Results In chow fed PF2 offspring from the maternal HF/HS (mHF/HS) lineage, total BA pool size was increased. No change in intrahepatic BA composition was observed. After HTFC diet, PF2H offspring showed decreased liver weight and liver weight to body weight ratio compared to PF2C offspring. PF2H offspring exhibited lower levels of intrahepatic triglyceride and free fatty acids. Conversely, PF2H offspring liver showed increased Sirius red staining. Conclusions Male offspring exposed to maternal obesogenic diet transmit a phenotype of altered BA homeostasis to their offspring. After exposure to a western diet, PF2H offspring exhibited worse fibrosis despite having less steatosis. Passage of these phenotypes through male offspring would suggest an epigenetic phenomenon as a mechanistic etiology. Future studies will evaluate the mechanism for transmission of maternal obesity driven changes in the liver across generations in the male lineage.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.