Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that regulates fatty acid transport and metabolism. Previous studies revealed that PPARα can affect bile acid metabolism; however, the mechanism by which PPARα 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 11β-hydroxy-3,20-dioxopregn-4-en-21-oic acid (20-fold) and 11β,20α-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 PPARα is an essential regulator of bile acid biosynthesis, transport, and secretion.
Highlights
Peroxisome proliferator-activated receptor ␣ (PPAR␣) is a nuclear receptor that regulates fatty acid transport and metabolism
To clarify the functional role of PPAR␣ in bile acid homeostasis, the present study investigated the change in endogenous metabolites and associated genes in Ppara-null mice during exposure to a cholic acid (CA) diet
Further gene expression analysis revealed that the bile acid disorder in CA-treated Ppara-null mice might be due to a deficiency in expression of the Abc transporters (Abcb11, ATPbinding cassette subfamily B member 4 (Abcb4), ATP-binding cassette subfamily A member 1 (Abca1), ATP-binding cassette subfamily G member 5 (Abcg5), and ATP-binding cassette subfamily G member 8 (Abcg8)) in the liver canliculus
Summary
Peroxisome proliferator-activated receptor ␣ (PPAR␣) is a nuclear receptor that regulates fatty acid transport and metabolism. Phospholipid homeostasis, as revealed by decreased serum lysophosphatidylcholine (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 (3.6fold), were disrupted in CA-treated Ppara-null mice. The hepatic levels of mRNA encoding transporters Abcb, Abcb, Abca, Abcg, and Abcg were diminished in Pparanull 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.—Li, F., A.
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