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.