ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity

Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.