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Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans

Lallukka, Susanna; Luukkonen, Panu K.; Zhou, You; Isokuortti, Elina; Leivonen, Marja; Juuti, Anne; Hakkarainen, Antti; Orho-Melander, Marju LU ; Lundbom, Nina and Olkkonen, Vesa M., et al. (2017) In Thrombosis and Haemostasis 117(2). p.286-294
Abstract

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... (More)

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.

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Contribution to journal
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published
subject
keywords
Adipose tissue, Fibrinogen, Inflammation, Insulin, Non-alcoholic fatty liver disease
in
Thrombosis and Haemostasis
volume
117
issue
2
pages
9 pages
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • scopus:85011031778
  • pmid:27929200
  • wos:000393358700011
ISSN
0340-6245
DOI
10.1160/TH16-09-0716
language
English
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yes
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1b96c90d-c4e0-4613-abb2-80cba526d8a6
date added to LUP
2017-02-16 15:49:06
date last changed
2018-11-21 21:29:54
@article{1b96c90d-c4e0-4613-abb2-80cba526d8a6,
  abstract     = {<p>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 (PNPLA3<sup>148MM/ MI</sup> vs PNPLA3<sup>148II</sup>). Liver fat content (<sup>1</sup>H-MRS) was similarly increased in ‘IR’ (13 ± 1%) and PNPLA3<sup>148MM/MI</sup> (12 ± 2%) as compared to ‘IS’ (6 ± 1%, p&lt;0.05) and PNPLA3<sup>148II</sup> (8 ± 1%, p&lt;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.</p>},
  author       = {Lallukka, Susanna and Luukkonen, Panu K. and Zhou, You and Isokuortti, Elina and Leivonen, Marja and Juuti, Anne and Hakkarainen, Antti and Orho-Melander, Marju and Lundbom, Nina and Olkkonen, Vesa M. and Lassila, Riitta and Yki-Järvinen, Hannele},
  issn         = {0340-6245},
  keyword      = {Adipose tissue,Fibrinogen,Inflammation,Insulin,Non-alcoholic fatty liver disease},
  language     = {eng},
  number       = {2},
  pages        = {286--294},
  publisher    = {F K Schattauer Verlag Gmbh},
  series       = {Thrombosis and Haemostasis},
  title        = {Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans},
  url          = {http://dx.doi.org/10.1160/TH16-09-0716},
  volume       = {117},
  year         = {2017},
}