Tumor Necrosis Factor a-Converting Enzyme Inhibition Reverses Hepatic Steatosis and Improves Insulin Sensitivity Markers and Surgical Outcome in Mice

Background: Hepatic steatosis is an established risk factor for complications following major hepatic resection. Pharmacological options to reverse steatosis prior to surgery, however, are lacking. We hypothesized that treatment with the pharmacologic tumor necrosis factor-a converting enzyme (TACE)-inhibitor Marimastat would reverse established steatosis, leading to improved outcome following hepatectomy. Methodology/Principal Findings: C57BL/6 male mice were fed a high fat diet for 9 weeks to establish obesity, hepatic steatosis and insulin resistance, and were administered either Marimastat or vehicle for an additional 2 or 4 weeks. Leptin deficient, hyperinsulinemic ob/ob mice were treated with Marimastat for 4 weeks. Hepatic steatosis was quantified by magnetic resonance spectroscopy and confirmed by histology. After two weeks, Marimastat-treated animals significantly improved surrogate markers for insulin sensitivity and liver histology, and experienced a 66% decrease in steatosis (P = 0.010). These findings were confirmed in ob/ob mice. Transcripts related to fatty acid synthesis were significantly downregulated in Marimastat-treated animals. Following pre-treatment with Marimastat or vehicle for two weeks, high fat fed C57BL/6 mice were subjected to two-thirds hepatectomy. Post-operative liver injury as quantified by serum aspartate aminotransferase levels and alanine aminotransferase levels was significantly decreased by 57% (P = 0.020) and 44% (P = 0.032) respectively, compared to controls. Conclusion/Significance: Treatment with the TACE-inhibitor Marimastat improved surrogate markers for insulin sensitivity and reversed steatosis in mouse models of diet-induced obesity and leptin deficiency, thereby attenuating post-operative injury following hepatectomy. This may suggest a potential therapeutic role in patients with fatty liver disease; especially those who need to undergo hepatic resection. Citation: de Meijer VE, Le HD, Meisel JA, Sharma AK, Popov Y, et al. (2011) Tumor Necrosis Factor a-Converting Enzyme Inhibition Reverses Hepatic Steatosis and Improves Insulin Sensitivity Markers and Surgical Outcome in Mice. PLoS ONE 6(9): e25587. doi:10.1371/journal.pone. 0025587 Editor: Massimo Federici, University of Tor Vergata, Italy Received February 13, 2011; Accepted September 8, 2011; Published September 27, 2011 Copyright: 2011 de Meijer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: VdM was recipient of fellowships from the foundations Stichting Profesor Michael-van Vloten Fonds (Venray, The Netherlands), VSBfonds (Utrecht, The Netherlands), Gerrit Jan Mulder Stichting (Rotterdam, The Netherlands), Prins Bernhard Cultuurfonds (Amsterdam, The Netherlands), and Dr Saal van Zwanenberg Stichting (Oss, The Netherlands). MP was supported by the Children’s Hospital Boston Surgical Foundation and The Vascular Biology Program (Boston, Massachusetts), and the National Institutes of Health (grant DK069621). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: A patent has been issued to Dr. Puder and Children’s Hospital Boston for the treatment of steatosis with the drug Marimastat. This manuscript shows the efficacy of this drug in a mouse model. The authors have no other proprietary information on the drug; therefore everything they know about it can be shared and is being shared with the reader of the manuscript. The drug is not owned by the authors or this institution. It was obtained from British Biotech (United Kingdom), and the drug and all rights were transferred to Vernalis (United Kingdom). Since Vernalis owns this drug, an interested party may contact the company and work out an agreement with them to obtain the drug. This agreement is the material transfer agreement. This is a common practice with proprietary drugs that are not on the market. Any and all information the authors have about the drug is open for disclosure from the authors but, as mentioned, is all in the manuscript. * E-mail: vdemeijer@hotmail.com