TY - JOUR
T1 - Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis
AU - Li, Hao
AU - Perino, Alessia
AU - Huang, Qingyao
AU - Von Alvensleben, Giacomo V.G.
AU - Banaei-Esfahani, Amir
AU - Velazquez-Villegas, Laura A.
AU - Gariani, Karim
AU - Korbelius, Melanie
AU - Bou Sleiman, Maroun
AU - Imbach, Jéromine
AU - Sun, Yu
AU - Li, Xiaoxu
AU - Bachmann, Alexis
AU - Goeminne, Ludger J.E.
AU - Gallart-Ayala, Hector
AU - Williams, Evan G.
AU - Ivanisevic, Julijana
AU - Auwerx, Johan
AU - Schoonjans, Kristina
N1 - Publisher Copyright:
© 2022 The Author(s)
PY - 2022/10/4
Y1 - 2022/10/4
N2 - 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.
AB - 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.
KW - BXD
KW - CES1C
KW - TUDCA
KW - bile acids
KW - gene-environment interaction
KW - high-fat diet
KW - metabolism
KW - mouse genetic reference population
KW - quantitative trait locus
KW - systems genetics
UR - https://www.scopus.com/pages/publications/85139032109
U2 - 10.1016/j.cmet.2022.08.015
DO - 10.1016/j.cmet.2022.08.015
M3 - 文章
C2 - 36099916
AN - SCOPUS:85139032109
SN - 1550-4131
VL - 34
SP - 1594-1610.e4
JO - Cell Metabolism
JF - Cell Metabolism
IS - 10
ER -