1. Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis.
- Author
-
Li, Hao, Perino, Alessia, Huang, Qingyao, Von Alvensleben, Giacomo V.G., Banaei-Esfahani, Amir, Velazquez-Villegas, Laura A., Gariani, Karim, Korbelius, Melanie, Bou Sleiman, Maroun, Imbach, Jéromine, Sun, Yu, Li, Xiaoxu, Bachmann, Alexis, Goeminne, Ludger J.E., Gallart-Ayala, Hector, Williams, Evan G., Ivanisevic, Julijana, Auwerx, Johan, and Schoonjans, Kristina
- Abstract
Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels. [Display omitted] • Multi-omics data and bile acid profiles were collected from ∼360 male BXD mice • Bile acid levels are strongly influenced by genetics and environment • Numerous genetic loci associate to bile acid abundance • CES1C is identified as a modulator for tauroursodeoxycholic acid plasma abundance Li et al. use the BXD mouse reference population to evaluate how genetics and diet regulate bile acid homeostasis. Through this integrated systems genetics approach, they mapped hundreds of genetic loci associated with bile acids and identified carboxylesterase 1C as a modulator for tauroursodeoxycholic acid plasma abundance. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF