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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease
Frederik Temmerman, Feng Chen, Louis Libbrecht, Ingrid Vander Elst, Petra Windmolders, Yuanbo Feng, Yicheng Ni, Humbert De Smedt, Frederik Nevens, Jos van Pelt
Frederik Temmerman, Ingrid Vander Elst, Petra Windmolders, Frederik Nevens, Jos van Pelt, Laboratory of Hepatology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Leuven, B 3000 Leuven, Belgium
Frederik Temmerman, Ingrid Vander Elst, Petra Windmolders, Frederik Nevens, Jos van Pelt, Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, B 3000 Leuven, Belgium
Feng Chen, Department of Radiology, The first Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Louis Libbrecht, Department of Pathology, Ghent University Hospital, B 9000 Ghent, Belgium
Yuanbo Feng, Yicheng Ni, Department of Imaging and Pathology, Faculty of Medicine, KU Leuven, B 3000 Leuven, Belgium
Humbert De Smedt, Laboratory of Molecular and Cellular Signalling, KU Leuven, B 3000 Leuven, Belgium
Jos van Pelt, Unit of Clinical Digestive Oncology, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, B 3000 Leuven, Belgium
Author contributions: Temmerman F performed the majority of experiments; Chen F, Feng Y and Ni Y performed the MRI and liver volume calculations; Libbrecht L performed histological interpretation; Vander Elst I and Windmolders P assisted with the animal experiments, performed molecular and protein analysis and processed tissue for histology; De Smedt H assisted in protein data analysis; Temmerman F, Nevens F and van Pelt J designed and coordinated the research, analyzed the data and wrote the paper.
Institutional animal care and use committee statement: All animal experiments were approved by the Ethical Committee for animal welfare (KU Leuven, P164/2010).
Conflict-of-interest statement: None of the authors report a potential conflict of interest regarding this work.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Jos van Pelt, Professor, Laboratory of Hepatology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Leuven, Geb. Onderwijs and Navorsing 1, 7e verd, bus 703, Herestraat 49, B 3000 Leuven, Belgium.
jos.vanpelt@kuleuven.be
Telephone: +32-16-330694 Fax: +32-16-330701
Received: February 27, 2017
Peer-review started: March 2, 2017
First decision: April 5, 2017
Revised: May 16, 2017
Accepted: June 1, 2017
Article in press: June 1, 2017
Published online: August 14, 2017
Processing time: 167 Days and 10.6 Hours
AIM
To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly.
METHODS
Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) (n = 10) or everolimus (EVR: 1 mg/kg per day) (n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated.
RESULTS
LV determination by MRI correlated excellent with the ex vivo measurements (r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis (P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels.
CONCLUSION
Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression.
Core tip: The continuous increase of liver cysts volume in polycystic-liver-disease (PCLD) leads to extensive hepatomegaly and portal hypertension, an indication for liver transplantation. The effect of mTOR-inhibition on liver volume (LV) in PCLD is unclear. We developed an accurate, non-invasive, MRI-based method to determine LV in a PCLD rat model. When treatment is started at the moment of extensive hepatomegaly (as in humans), the mTOR inhibitor everolimus halt disease progression and also of the development of fibrosis in this model. We speculate that everolimus, given after kidney transplantation in patients with PCLD, can prevent the development of symptomatic hepatomegaly.
