TY - JOUR T1 - Disrupted Murine Gut to Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.116.236935 SP - jpet.116.236935 AU - Edwin C. Y. Chow AU - Holly P. Quach AU - Yueping Zhang AU - Jason Z. Y. Wang AU - David C. Evan AU - Albert P Li AU - Jose Silva AU - Rommel G. Tirona AU - Yurong Lai AU - K. Sandy Pang Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/early/2016/10/27/jpet.116.236935.abstract N2 - The humanized liver mouse model is increasingly being exploited for human drug metabolism studies. However, its model stability, inter-communication between human hepatocytes and mouse non-parenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expression has not been investigated. We examined these issues in FRGN [Fah(-/-), Rag2(-/-), and IL-2rg(-/-) on NOD background] and chimeric mice: mFRGN, and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids), but lower TGFBR2 mRNA expression (10%) in human hepatocytes and other proliferative markers in mouse non-parenchymal cells (Tgf-β1) and cholangiocytes (Tgr5), suggestive of irregular regeneration processes in hFRGN livers. Changes in the murine intestine, kidney, and brain of hFRGN mice: in particular, induction of intestinal Fxr genes: Fgf15, Ibabp, Shp, and Ost-α, were observed. Proteomics revealed persistence of remnant murine proteins (Cyp7a1, other enzymes, and transporters) in hFRGN livers and likelihood of mouse activity. When compared to normal human liver tissues, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tβMCA- and tαMCA-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver FGFR4, as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, questioning use of the preparation for drug metabolism studies. ER -