Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Timp3, possibly through its regulation of TACE, appears to have a role in the pathogenesis of fatty liver disease associated with obesity.
Menghini
Rossella
R
Department of Internal Medicine, University of Rome "Tor Vergata," Rome, Italy.
Menini
Stefano
S
Amoruso
Roberta
R
Fiorentino
Loredana
L
Casagrande
Viviana
V
Marzano
Valeria
V
Tornei
Federica
F
Bertucci
Pierfrancesco
P
Iacobini
Carla
C
Serino
Matteo
M
Porzio
Ottavia
O
Hribal
Marta L
ML
Folli
Franco
F
Khokha
Rama
R
Urbani
Andrea
A
Lauro
Renato
R
Pugliese
Giuseppe
G
Federici
Massimo
M
D051722:ADAM Proteins / Q000172:deficiency / Q000378:metabolism; D000072198:ADAM17 Protein; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D015434:Panniculitis / Q000235:genetics* / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
D004041:Dietary Fats; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse