Metabolomics reveals an essential role for peroxisome proliferator-activated receptor ? in bile acid homeostasis.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a nuclear receptor that regulates fatty acid transport and metabolism. Previous studies revealed that PPAR? can affect bile acid metabolism; however, the mechanism by which PPAR? regulates bile acid homeostasis is not understood. In this study, an ultraperformance liquid chromatography coupled with electrospray ionization qua dru pole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics approach was used to profile metabolites in urine, serum, and bile of wild-type and Ppara-null mice following cholic acid (CA) dietary challenge. Metabolomic analysis showed that the levels of several serum bile acids, such as CA (25-fold) and taurocholic acid (16-fold), were significantly increased in CA-treated Ppara-null mice compared with CA-treated wild-type mice. Phospholipid homeostasis, as revealed by decreased serum lysophos phati dylcholine (LPC) 16:0 (1.6-fold) and LPC 18:0 (1.6-fold), and corticosterone metabolism noted by increased urinary excretion of 11?-hydroxy-3,20-dioxopregn-4-en-21-oic acid (20-fold) and 11?,20?-dihydroxy-3-oxo-pregn-4-en-21-oic acid (3.6-fold), were disrupted in CA-treated Ppara-null mice. The hepatic levels of mRNA encoding transporters Abcb11, Abcb4, Abca1, Abcg5, and Abcg8 were diminished in Ppara-null mice, leading to the accumulation of bile acids in the liver during the CA challenge. These observations revealed that PPAR? is an essential regulator of bile acid biosynthesis, transport, and secretion.

SUBMITTER: Li F 

PROVIDER: S-EPMC3540854 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other