Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice

Fernández-Barrena, Maite G.; Monte, Maria J.; Latasa, Maria U.; Uriarte, Iker; Vicente, Eva; Chang, Haisul C.Y.; Rodriguez-Ortigosa, Carlos M.; Elferink, Ronald Oude; Berasain, Carmen; Marin, Jose J.G.; Prieto, Jesus; Ávila, Matias A.

doi:10.1016/j.jhep.2011.05.031

« Previous Next »Journal of Hepatology
Volume 56, Issue 2 , Pages 367-373, February 2012

Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice

Maite G. Fernández-Barrena
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
Maria J. Monte
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
Maria U. Latasa
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
Iker Uriarte
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
Eva Vicente
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
Haisul C.Y. Chang
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
Carlos M. Rodriguez-Ortigosa
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
Ronald Oude Elferink
- AMC Liver Center, Academic Medical Center, 1105BK Amsterdam, The Netherlands
Carmen Berasain
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
Jose J.G. Marin
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
Jesus Prieto
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Corresponding authors. Address: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain. Tel.: +34 948 194700x4003; fax: +34 948 194717.
Matias A. Ávila
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
- Corresponding authors. Address: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Avda. Pio XII, n55, 31008 Pamplona, Spain. Tel.: +34 948 194700x4003; fax: +34 948 194717.

Received 15 February 2011; received in revised form 10 May 2011; accepted 23 May 2011. published online 13 July 2011.

Background & Aims

Bile acids (BA) are increasingly recognized as important modulators of liver regeneration. Increased enterohepatic BA flux has been proposed to generate specific signals that activate hepatocyte proliferation after partial hepatectomy (PH). We have investigated the role of the BA membrane transporter Mrp3 (Abcc3), which is expressed in the liver and gut, in the hepatic growth response elicited by BA and in liver regeneration after PH.

Methods

Liver growth and regeneration, and the expression of growth-related genes, were studied in Mrp3^+/+ and Mrp3^−/− mice fed a cholic acid (CA) supplemented diet and after 2/3 PH. Activation of the BA receptor FXR was measured in mice after in vivo transduction of the liver with a FXR-Luciferase reporter plasmid. BA levels were measured in portal serum and liver tissue by high performance liquid chromatography-tandem mass spectrometry.

Results

Liver growth elicited by CA feeding was significantly reduced in Mrp3^−/− mice. These animals showed reduced FXR activation in the liver after CA administration and decreased portal serum levels of BA. Liver regeneration after PH was significantly delayed in Mrp3-deficient mice. Proliferation-related gene expression and peak DNA synthesis in Mrp3^−/− mice occurred later than in wild types, coinciding with a retarded elevation in intra-hepatic BA levels.

Conclusions

Lack of Abcc3 expression markedly impairs liver growth in response to BA and after PH. Our data suggest that Mrp3 plays a non-redundant role in the regulation of BA flux during liver regeneration.

Abbreviations: BA, bile acids, PH, partial hepatectomy, Mrp3, multi drug resistance-associated protein 3, CA, cholic acid, FXR, farnesoid X receptor, EGF, epidermal growth factor, Cyp7a1, cholesterol 7-alpha hydroxylase, Ntcp, Na⁺-taurocholate cotransporting protein, Bsep, bile salt export pump, Asbt, apical sodium-dependent bile acid transporter, Ost, organic solute transporter, BrdU, 5′-Br-2′-deoxyuridine, PCNA, proliferative cell nuclear antigen, EGFR, epidermal growth factor receptor, HB-EGF, heparin-binding EGF, TGFα, transforming growth factor α, Fgf15, fibroblast growth factor 15, BDL, bile duct ligation, TC, taurocholic acid, TMC, tauro-muricholic acid, TCDC, taurochenodeoxycholic acid, TUDC, tauro-urso-deoxycholic acid