SAT007 Excess Bile Acids Can Compensate To Promote Regeneration In Constitutive Androstane Receptor Knockout Mice

Abstract

Abstract Disclosure: W. Zhou: None. U.V. Chembazhi: None. J. Huang: None. S. Bangru: None. A.E. Dean: None. A. Kalsotra: None. D.A. Rudnick: None. S. Anakk: None. The liver plays a key role for the metabolism of nutrients and xenobiotics. Nuclear receptor constitutive androstane receptor (CAR) regulates the transcription of detoxification and proliferation genes. The liver can also regenerate, which can be tested using a model of 2/3rd partial hepatectomy (PHx). We investigated the role for CAR during liver regeneration by mining publicly available single-cell RNA seq data after PHx. Car and its target expression was enriched in hypermetabolic hepatocytes, which was unexpected since based on previous studies we anticipated a proliferative role for CAR. We also examined liver weight, hepatocyte proliferation, and levels of bile acid (BAs) and liver enzymes in Car knockout (CarKO) and wild-type (WT) mice after PHx, and found them comparable between the two genotypes. Intriguingly, we noted a dramatic BA overload and concomitant changes in the expression of genes responsible for BA synthesis and detoxification in CarKO mice after PHx. This led us to speculate if the BA excess observed in CarKO mice after PHx promoted regeneration. When this excess BAs was reduced with a resin treatment in CarKO mice, we found deficits in proliferation and Yes-associated protein signaling demonstrating that elevated BAs act as mitogens to counteract the regenerative defects in CarKO livers. Presentation: Saturday, June 17, 2023