Metabolomics reveals the mechanism of bile salt export pump mutation related-cholestasis and its novel physiological functions in vivo

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NCI	PROTEOM-4

* FARE Award Winner

Authors

• F Li
• Y Zhang
• AD Patterson
• KW Krausz
• JD Schuetz
• FJ Gonzalez

Abstract

Bile Salt Export Pump (Bsep), encoded by ABCB11, is the primary bile salt transporter located at the canalicular domain of hepatocytes. Mutations in the ABCB11 gene result in progressive familial intrahepatic cholestasis type 2 and benign recurrent intrahepatic cholestasis type 2. In an effort to comprehensively understand the physiological functions of Bsep and its mutation related-cholestasis, metabolomics using ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry was conducted on urine, serum and liver homogenate from wild-type and Bsep-null mice. Metabolomic analysis further showed that 34 endogenous metabolites were significantly modulated in Bsep-null mice. In addition to an increase in bile acids, the metabolomic approach also identified biomarkers for Bsep deficiency previously unassociated with Bsep function: 1) Elevated medium-chain dicarboxylic acids in serum suggested impaired mitochondrial function. 2) Increased urinary glycine conjugates and cresol metabolites indicated significant metabolic perturbation in the intestine. 3) An increase in two lysophophatidylcholines (LPC 16:1 and LPC 18:1) in serum and two corticosterone derivatives (HDOPA and DHOPA) in urine demonstrated a defect in phospholipid and corticosterone metabolism. This study suggests that elevated liver bile acids and impaired mitochondrial function are responsible in part for Bsep mutation-induced cholestasis.

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