title: ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity.
abstract: Increased prevalence of obesity is paralleled by an increase in non-alcoholic steatohepatitis (NASH). We previously found that the expression of ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) is enhanced in expanding adipose tissue. However, no information is available on a potential role in liver pathology. We studied the effect of ADAMTS5 deficiency on NASH in mice.
  
  
  
  Wild-type (Adamts5+/+) and deficient (Adamts5-/-) mice were kept on a standard- or high-fat diet (HFD) for 15 weeks. Alternatively, steatohepatitis was induced with methionine/choline-deficient (MCD) diet.
  
  
  
  HFD feeding resulted in comparable body weights for both genotypes, but Adamts5-/-mice had approximately 40% lower liver weight (P = 0.0004). In the Adamts5-/-mice, the HFD as well as the MCD diet consistently induced less NASH with less fibrosis. The deteriorating effect of ADAMTS5 on the liver during diet-induced obesity may be due, at least in part, to proteolytic cleavage of the matrix components syndecan-1 and versican, thereby enhancing hepatic triglyceride clearance from the circulation. Plasma lipid levels were elevated in obese Adamts5-/-mice. There was no clear effect of ADAMTS5 deficiency on glycaemia or glucose tolerance, whereas insulin sensitivity was somewhat improved. Furthermore, Adamts5-/-mice were protected from hepatic mitochondrial dysfunction, as indicated by increased mitochondrial respiratory chain complex activity, higher ATP levels and higher expression of antioxidant enzymes.
  
  
  
  Absence of ADAMTS5 preserves liver integrity in a diet-induced obesity model. Selective targeting of ADAMTS5 could provide a new therapeutic strategy for treatment/prevention of NASH.
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Dries
authors.initials: D
authors.lastname: Bauters
authors.affiliation: Lab of Hepatology, University of Leuven, Leuven, Belgium.|Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Spincemaille
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Lotte
authors.initials: L
authors.lastname: Geys
authors.affiliation: Department of Hepatology and Metabolic Center, University Hospitals Leuven, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.|Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vermeersch
authors.affiliation: Department of Pathology, Hôpital Beaujon, Clichy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Scroyen
authors.affiliation: Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Henri R
authors.initials: HR
authors.lastname: Lijnen
mesh_terms: D000071116:ADAMTS5 Protein / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D015870:Gene Expression; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology*; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D014280:Triglycerides / Q000097:blood
chemical_list: D000975:Antioxidants; D014280:Triglycerides; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse
keywords: 
  NASH
  ; aggrecanase-2; extracellular matrix; obesity