ADAMTS13 deficiency promotes microthrombosis in a murine model of diet-induced liver steatosis.
ADAMTS13 cleaves ultralarge multimeric von Willebrand Factor (VWF), thereby preventing formation of platelet-rich microthrombi. ADAMTS13 is mainly produced by hepatic stellate cells, and numerous studies have suggested a functional role of ADAMTS13 in the pathogenesis of liver diseases. The aim of our study was to investigate a potential role of ADAMTS13 in formation of hepatic microthrombi and development of non-alcoholic steatohepatitis (NASH), and furthermore to evaluate whether plasmin can compensate for the absence of ADAMTS13 in removal of thrombi. Therefore, we used a model of high-fat diet-induced steatosis in Adamts13 deficient (Adamts13-/-) and wild-type (WT) control mice. Microthrombi were more abundant in the liver of obese Adamts13-/-as compared to obese WT or to lean Adamts13-/-mice. Obese Adamts13-/-mice displayed lower platelet counts and higher prevalence of ultra-large VWF multimers. Hepatic plasmin-α2-antiplasmin complex levels were comparable for obese WT and Adamts13-/-mice and were lower for lean Adamts13-/-than WT mice, not supporting marked activation of the fibrinolytic system. High fat diet feeding, as compared to normal chow, resulted in enhanced liver triglyceride levels for both genotypes (p < 0.0001) and steatosis (p < 0.0001 for WT mice, p = 0.002 for Adamts13-/-mice) without differences between the genotypes. Expression of markers of inflammation, oxidative stress, steatosis and fibrosis was affected by diet, but not by genotype. Thus, our data confirm that obesity promotes NASH, but do not support a detrimental role of ADAMTS13 in its development. However, Adamts13 deficiency in obese mice promotes hepatic microthrombosis, whereas a compensatory role of plasmin in removal of microthrombi in the absence of ADAMTS13 could not be demonstrated.
Lotte
L
Geys
Dries
D
Bauters
Elien
E
Roose
Claudia
C
Tersteeg
Karen
K
Vanhoorelbeke
Marc F
MF
Hoylaerts
H. R. Lijnen, Center for Molecular and Vascular Biology, KU Leuven, Campus Gasthuisberg, CDG, Herestraat 49, Box 911, B-3000 Leuven, Belgium, Tel.: +32 16 372053, Fax: +32 16 345990, E-mail: roger.lijnen@med.kuleuven.be.
Roger H
RH
Lijnen
Ilse
I
Scroyen
D000071120:ADAMTS13 Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001777:Blood Coagulation; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D009765:Obesity / Q000209:etiology; D018384:Oxidative Stress; D010641:Phenotype; D013927:Thrombosis / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D018836:Inflammation Mediators; D014280:Triglycerides; D000979:alpha-2-Antiplasmin; C037742:plasmin-plasmin inhibitor complex; D014841:von Willebrand Factor; D005341:Fibrinolysin; C502939:ADAMTS13 protein, mouse; D000071120:ADAMTS13 Protein
ADAMTS13; microthrombosis; non-alcoholic fatty liver disease; obesity