Tissue Inhibitor of Metalloproteinase 3 Deficiency Causes Hepatic Steatosis and Adipose Tissue Inflammation in Mice
Copyright policy )Tissue Inhibitor of Metalloproteinase 3 Deficiency Causes Hepatic Steatosis and Adipose Tissue Inflammation in Mice
Obesity-driven, low-grade inflammation affects systemic metabolic function and can lead to insulin resistance, hepatic steatosis, and atherosclerosis. Decreased expression of tissue inhibitor of metalloproteinase 3 (Timp3) is a catalyst for insulin resistance and inflammation. Timp3 is a natural inhibitor of matrix metalloproteinases, tumor necrosis factor-alpha-converting enzyme (TACE), and vascular endothelial growth factor receptor 2, and therefore could affect signaling processes involved in inflammation and angiogenesis.We assessed the effects of Timp3 on inflammation, tissue remodeling, and intermediary metabolism in mice, under conditions of environmental stress (high-fat diet), genetic predisposition to insulin resistance (insulin receptor [Insr] haploinsufficiency), and varying levels of inflammation (Timp3 or Tace deficiencies). Metabolic tests, immunohistochemistry, real-time polymerase chain reaction, and immunoblotting were used to compare data from wild-type, Insr(+/-), Timp3(-/-), Insr(+/-)Timp3(-/-), and Insr(+/-)Tace(+/-) mice placed on high-fat diets for 10 weeks.Insr(+/-)Timp3(-/-) mice showed a higher degree of adipose and hepatic inflammation compared with wild-type, Insr(+/-), Timp3(-/-), and Insr(+/-)Tace(+/-) mice. In particular, the Insr(+/-)Timp3(-/-) mice developed macrovesicular steatosis and features of severe nonalcoholic fatty liver disease, including lobular and periportal inflammation, hepatocellular ballooning, and perisinusoidal fibrosis. These were associated with increased expression of inflammatory and steatosis markers, including suppressor of cytokine signaling 3 and stearoyl CoA desaturase 1, in both liver and adipose tissue. Interestingly, Insr(+/-)Tace(+/-) mice had a nearly opposite phenotype.Timp3, possibly through its regulation of TACE, appears to have a role in the pathogenesis of fatty liver disease associated with obesity.
- University of Toronto Canada
- The University of Texas at Austin United States
- University of Rome Tor Vergata Italy
- Roma Tre University Italy
- Sapienza University of Rome Italy
ADAM Protein, Animals; Obesity; Adipose Tissue, White; Disease Models, Animal; Fatty Liver; Mice; Liver Cirrhosis; Stearoyl-CoA Desaturase; Mice, Knockout; Suppressor of Cytokine Signaling Proteins; Tissue Inhibitor of Metalloproteinase-3; ADAM Proteins; Panniculitis; Mice, Inbred C57BL; Genetic Predisposition to Disease; Insulin Resistance; Dietary Fats, Liver Cirrhosis, Panniculitis, Liver Cirrhosi, Knockout, Adipose Tissue, White, 610, White, Suppressor of Cytokine Signaling Proteins, ADAM17 Protein, Inbred C57BL, Mice, Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, 615, Suppressor of Cytokine Signaling Protein, Animals, Genetic Predisposition to Disease, Obesity, Panniculiti, Mice, Knockout, Tissue Inhibitor of Metalloproteinase-3, Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITA' MOTORIE, Animal, Settore MED/09 - MEDICINA INTERNA, Dietary Fats, Fatty Liver, Mice, Inbred C57BL, ADAM Proteins, Disease Models, Animal, Adipose Tissue, Suppressor of Cytokine Signaling 3 Protein, Disease Models, Gastroenterology, low grade inflammation, TIMP3, tissue inhibitor of metalloproteinase 3, TACE, tumor necrosis alfa converting enzyme, insulin receptor knock out, timp3 knock out , mouse, Insulin Resistance, Stearoyl-CoA Desaturase
ADAM Protein, Animals; Obesity; Adipose Tissue, White; Disease Models, Animal; Fatty Liver; Mice; Liver Cirrhosis; Stearoyl-CoA Desaturase; Mice, Knockout; Suppressor of Cytokine Signaling Proteins; Tissue Inhibitor of Metalloproteinase-3; ADAM Proteins; Panniculitis; Mice, Inbred C57BL; Genetic Predisposition to Disease; Insulin Resistance; Dietary Fats, Liver Cirrhosis, Panniculitis, Liver Cirrhosi, Knockout, Adipose Tissue, White, 610, White, Suppressor of Cytokine Signaling Proteins, ADAM17 Protein, Inbred C57BL, Mice, Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, 615, Suppressor of Cytokine Signaling Protein, Animals, Genetic Predisposition to Disease, Obesity, Panniculiti, Mice, Knockout, Tissue Inhibitor of Metalloproteinase-3, Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITA' MOTORIE, Animal, Settore MED/09 - MEDICINA INTERNA, Dietary Fats, Fatty Liver, Mice, Inbred C57BL, ADAM Proteins, Disease Models, Animal, Adipose Tissue, Suppressor of Cytokine Signaling 3 Protein, Disease Models, Gastroenterology, low grade inflammation, TIMP3, tissue inhibitor of metalloproteinase 3, TACE, tumor necrosis alfa converting enzyme, insulin receptor knock out, timp3 knock out , mouse, Insulin Resistance, Stearoyl-CoA Desaturase
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