Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humansFinancial support: This study was supported by University of Helsinki, the Doctoral Programme in Clinical Research and personal grants (S. Lallukka) from Diabetes Research Foundation, Biomedicum Helsinki Foundation and Orion Research Foundation, research grants (H. Yki-Järvinen) from the Academy of Finland, EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant no. 115372), EU H2020 project ‘Elucidating Pathways of Steatohepatitis’ (EPoS), grant no. 634413, the Sigrid Juselius Foundation, the EVO grant from the Finnish government, and additionally supported by the Swedish Research Council, the Swedish Heart and Lung foundation, and the NovoNordisk Foundation (M. Orho-Melander).
Received:21 September 2016
Accepted after minor revision:11 November 2016
13 November 2017 (online)
Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant (‘IR’) versus insulin-sensitive (‘IS’)] and PNPLA3 genotype (PNPLA3148MM/MI vs PNPLA3148II). Liver fat content (1H-MRS) was similarly increased in ‘IR’ (13 ± 1 %) and PNPLA3148MM/MI (12 ± 2 %) as compared to ‘IS’ (6 ± 1 %, p < 0.05) and PNPLA3148II (8 ± 1 %, p < 0.05), respectively. FVIII, FIX, FXIII, fibrinogen and VWF:RCo activities were increased, and PT and APTT shortened in ‘IR’ versus ‘IS’, in contrast to these factors being similar between PNPLA3148MM/MI and PNPLA3148II groups. In subjects undergoing a liver biopsy and entirely lacking the I148M variant, insulin-resistant subjects had higher hepatic expression of F8, F9 and FGG than equally obese insulin-sensitive subjects. Expression of pro-inflammatory genes in adipose tissue correlated positively with PT (% of normal), circulating FVIII, FIX, FXI, VWR:RCo and fibrinogen, and expression of anti-inflammatory genes negatively with PT (%), FIX and fibrinogen. We conclude that obesity/insulin resistance rather than an increase in liver fat is associated with a procoagulant plasma profile. This reflects adipose tissue inflammation and increased hepatic production of coagulation factors and their susceptibility for activation.
Supplementary Material to this article is available online at www.thrombosis-online.com.
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