HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/G1011    most recent 00047.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Alwayn, I. P. J. Articles by Puder, M. Search for Related Content PubMed PubMed Citation Articles by Alwayn, I. P. J. Articles by Puder, M.

TRANSLATIONAL PHYSIOLOGY

Inhibition of matrix metalloproteinases increases PPAR- and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model

Departments of ¹Surgery and the Vascular Biology Program, ²Pharmacy, and ³Radiology, Children's Hospital Boston; ⁴Department of Medicine, Beth Israel Deaconess Medical Center; ⁵Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and ⁶Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands

Submitted 25 January 2006 ; accepted in final form 7 July 2006

ABSTRACT

Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF- induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF- converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor- (PPAR-), higher levels of serum IL-6, and decreased levels of serum TNF- receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR- in the HCD+MAR group. PPAR- is a transcription factor involved in -oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR- or IL-6, respectively.

matrix metalloproteinase; nonalcoholic fatty liver disease; TNF-; PPAR-

This article has been cited by other articles:

				N. Anderson and J. Borlak Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis Pharmacol. Rev., September 1, 2008; 60(3): 311 - 357. [Abstract] [Full Text] [PDF]