title: Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans.
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/MIvs 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/MIand PNPLA3148IIgroups. 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.
authors.affiliation: Susanna Lallukka, MD, Minerva Institute for Medical Research, Biomedicum Helsinki 2U, Room DP02b, Tukholmankatu 8, 00290 Helsinki, Finland, Tel.: +358 2941 25708, Fax: +358 9 471 71896, E-mail: susanna.lallukka@helsinki.fi.
authors.forename: Susanna
authors.initials: S
authors.lastname: Lallukka
authors.forename: Panu K
authors.initials: PK
authors.lastname: Luukkonen
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.forename: Elina
authors.initials: E
authors.lastname: Isokuortti
authors.forename: Marja
authors.initials: M
authors.lastname: Leivonen
authors.forename: Anne
authors.initials: A
authors.lastname: Juuti
authors.forename: Antti
authors.initials: A
authors.lastname: Hakkarainen
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Nina
authors.initials: N
authors.lastname: Lundbom
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D009765:Obesity / Q000097:blood* / Q000175:diagnosis; D010314:Partial Thromboplastin Time; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011517:Prothrombin Time; D015854:Up-Regulation; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D015415:Biomarkers; D001779:Blood Coagulation Factors; D016207:Cytokines; D018836:Inflammation Mediators; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: Adipose tissue; fibrinogen; inflammation; insulin; non-alcoholic fatty liver disease