Ruolo della diade TACE/Timp3 nell'insulino-resistenza e nella steatosi epatica

Tumor necrosis factor a–converting enzyme (TACE) and its physiological inhibitor Timp-3 were recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in mice fed a high fat diet, particularly in livers but also in muscle and adipose tissue, compared to littermates fed a regular diet. In mouse hepatocytes, myocytes and adipocytes TACE activity was triggered by several metabolic stimuli, such as palmitic acid, lipopolysaccharide, high glucose and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of Akt, GSK3 and FoxO1, the major controllers of gluconeogenesis and lipogenesis. To test the role of TACE activation in vivo, we used Timp3 null mice which have higher TACE activity compared with wild type (WT) mice. Timp3-/- mice fed a high fat diet for 20 weeks were glucose-intolerant and insulin-resistant; they showed macrovescicular steatosis and ballooning degeneration compared to WT mice, which presented only microvescicular steatosis. Shotgun proteomic analysis revealed that Timp3-/- liver has a significant differential expression of 38 proteins, including lower levels of adenosine kinase (ADK), methionine adenosyltransferase I/III (MATI/III) and glycine N-methyltransferase (GNMT), and higher levels of liver fatty acid-binding protein 1 (FABP-1). These changes in protein levels were also observed in hepatocytes infected with an adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, trygliceride synthesis and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3-/- compared to WT mice. So we have identified novel mechanisms governed by the TACE/ Timp3 dyad involved in the determination of insulin resistance and liver steatosis during overfeeding in mice.