Non‐alcoholic fatty liver disease (NAFLD) is a highly prevalent disease affecting approximately one‐quarter of the global population. It has been estimated that up to 20–25% of this population progresses into advanced liver disease. Numerous researches performed in both humans and animal models have revealed that maternal obesity is a risk factor for the development of NAFLD and its progression to non-alcoholic steatohepatitis (NASH). The current study conducted in experimental model of maternal obesity demonstrated that the offspring develop periportal fibrosis and inflammation with associated changes in bile acid (BA) homeostasis. The researchers further determined the variations in BA homeostasis and examined disease progression in offspring exposed to a western diet.

The study included female C57Bl6 experimental animals who were fed chow (CON) or high fat, high sucrose (HF/HS) diet for 6 weeks to induce obesity and then they were bred with lean males. Further, the mating of F1 and F2 female offspring to lean males was done to develop the F2 and F3 generations, respectively. Offspring were then fed chow or high trans‐fat, cholesterol, fructose (HTFC) diet for 16 weeks to induce progressive NAFLD. These offspring were then undergone metabolic and histopathologic analyses.

The results of the study showed that total BA pool size was increased and intrahepatic BA composition was altered with related changes in expression of genes intricate in bile acid metabolism such as increased Cyp7a1, Cyp27a1 in chow fed F1 offspring from the maternal HF/HS (mHF/HS) lineage. BA pool size increased in mCON lineage and paradoxically decreased in mHF/HS lineage, in F1 offspring fed HTFC. Determination of specific bile acids in liver revealed a different intrahepatic BA pool composition, with reduced farnesoid X receptor (FXR) agonists and increased FXR antagonists in offspring from the mHF/HS lineage. However, BA pool size was found to be similar in the F2 and F3 generation offspring. F1 offspring from the mHF/HS displayed increased steatosis and intrahepatic triglyceride whereas no difference in steatosis was seen in the F2 and F3 generations. On the contrary, inflammation and fibrosis were reduced in F1 offspring from the mHF/HS lineage in contrast to mCON while F2 and F3 offspring from the same lineage showed less fibrosis.

Thus, the study concluded that administration of maternal HF/HS diet can cause alterations in the offspring that involves periportal fibrosis and inflammation. Moreover, based on these findings, it was revealed that F1 offspring of obese dams had worse steatosis but less inflammation and fibrosis when they were fed with western diet.  Although the study showed related changes in BA homeostasis, establishing a causal link is yet not well understood. There is a need to conduct further studies that can evaluate the mechanism of pathological changes occurring in BA homeostasis and their association with observed phenotype.

Source: Thompson MD, Derse A, LA Ferey J,  Reid M, Xie Y, Christ  M, Chatterjee D, Moley KH, Davidson NO. Impact of Maternal Obesity on Offspring Bile Acid Homeostasis and Pathologic Progression in Non‐Alcoholic Fatty Liver Disease. The FASEB Journal. 2019 April;33(S1): 496.41-496.41.