title: Tumor necrosis factor α-converting enzyme inhibition reverses hepatic steatosis and improves insulin sensitivity markers and surgical outcome in mice.
abstract: 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-α converting enzyme (TACE)-inhibitor Marimastat would reverse established steatosis, leading to improved outcome following hepatectomy.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Surgery and The Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America. vdemeijer@hotmail.com
authors: Vincent E
authors: VE
authors: de Meijer
authors: Hau D
authors: HD
authors: Le
authors: Jonathan A
authors: JA
authors: Meisel
authors: Anisha K
authors: AK
authors: Sharma
authors: Yury
authors: Y
authors: Popov
authors: Mark
authors: M
authors: Puder
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D054392:Adipokines / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D025461:Feedback, Physiological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006498:Hepatectomy / Q000009:adverse effects; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000172:deficiency; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D054392:Adipokines; D015415:Biomarkers; D005227:Fatty Acids; D006877:Hydroxamic Acids; D007328:Insulin; D020738:Leptin; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019717:Tissue Inhibitor of Metalloproteinase-3; C100342:marimastat; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse