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Thromb Haemost 2017; 117(02): 286-294
DOI: 10.1160/TH16-09-0716
Coagulation and Fibrinolysis
Schattauer GmbH

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

Susanna Lallukka
1   Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
2   Minerva Foundation Institute for Medical Research, Helsinki, Finland
,
Panu K. Luukkonen
1   Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
2   Minerva Foundation Institute for Medical Research, Helsinki, Finland
,
You Zhou
2   Minerva Foundation Institute for Medical Research, Helsinki, Finland
,
Elina Isokuortti
1   Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
2   Minerva Foundation Institute for Medical Research, Helsinki, Finland
,
Marja Leivonen
3   Department of Surgery, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
,
Anne Juuti
3   Department of Surgery, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
,
Antti Hakkarainen
4   Helsinki Medical Imaging Center, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
,
Marju Orho-Melander
5   Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
,
Nina Lundbom
4   Helsinki Medical Imaging Center, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
,
Vesa M. Olkkonen
2   Minerva Foundation Institute for Medical Research, Helsinki, Finland
,
Riitta Lassila
6   Coagulation Disorders Unit, Department of Hematology, and HUSLAB Laboratory Services, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
,
Hannele Yki-Järvinen
1   Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
2   Minerva Foundation Institute for Medical Research, Helsinki, Finland
› Author Affiliations Financial 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).
Further Information

Publication History

Received:21 September 2016

Accepted after minor revision:11 November 2016

Publication Date:
13 November 2017 (online)

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Summary

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.

Keywords

Adipose tissue - inflammation - fibrinogen - insulin - Non-alcoholic fatty liver disease

 

  • References

  • 1 European Association for the Study of the Liver (EASL). Electronic address: easloffice@easloffice.eu, European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-1402.
    CrossrefPubMedGoogle Scholar
  • 2 Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 02: 901-910.
    CrossrefPubMedGoogle Scholar
  • 3 Horvei LD, Grimnes G, Hindberg K. et al. C-reactive protein, obesity, and the risk of arterial and venous thrombosis. J Thromb Haemost 2016; 14: 1561-1571.
    CrossrefPubMedGoogle Scholar
  • 4 Romeo S, Kozlitina J, Xing C. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-1465.
    CrossrefPubMedGoogle Scholar
  • 5 Kotronen A, Johansson LE, Johansson LM. et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 2009; 52: 1056-1060.
    CrossrefPubMedGoogle Scholar
  • 6 He S, McPhaul C, Li JZ. et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010; 285: 6706-6715.
    CrossrefPubMedGoogle Scholar
  • 7 Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011; 53: 1883-1894.
    CrossrefPubMedGoogle Scholar
  • 8 Lallukka S, Sevastianova K, Perttila J. et al. Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3. Diabetologia 2013; 56: 886-892.
    CrossrefPubMedGoogle Scholar
  • 9 Xu H, Barnes GT, Yang Q. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830.
    CrossrefPubMedGoogle Scholar
  • 10 Weisberg SP, Hunter D, Huber R. et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116: 115-124.
    CrossrefPubMedGoogle Scholar
  • 11 Kanda H, Tateya S, Tamori Y. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494-1505.
    CrossrefPubMedGoogle Scholar
  • 12 Marder V, Aird W, Bennett J, Schulman S, White GI. editors Hemostasis and thrombosis: Basic principles and clinical practice. 6th ed. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.
    PubMedGoogle Scholar
  • 13 Wion KL, Kelly D, Summerfield JA. et al. Distribution of factor VIII mRNA and antigen in human liver and other tissues. Nature 1985; 317: 726-729.
    CrossrefPubMedGoogle Scholar
  • 14 Cigolini M, Targher G, Agostino G. et al. Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men--role of the metabolic syndrome. Thromb Haemost 1996; 76: 69-73.
    PubMedGoogle Scholar
  • 15 Kotronen A, Joutsi-Korhonen L, Sevastianova K. et al. Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease. Liver Int 2011; 31: 176-183.
    CrossrefPubMedGoogle Scholar
  • 16 Targher G, Bertolini L, Scala L. et al. Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. role of visceral adipose tissue. Diabet Med 2005; 22: 1354-1358.
    CrossrefPubMedGoogle Scholar
  • 17 Bertina RM. Elevated clotting factor levels and venous thrombosis. Pathophysiol Haemost Thromb 2003; 33: 395-400.
    CrossrefPubMedGoogle Scholar
  • 18 Lisman T, Caldwell SH, Burroughs AK. et al. Coagulation in Liver Disease Study Group.Hemostasis and thrombosis in patients with liver disease: The ups and downs. J Hepatol 2010; 53: 362-371.
    CrossrefPubMedGoogle Scholar
  • 19 Weisberg SP, McCann D, Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808.
    CrossrefPubMedGoogle Scholar
  • 20 Yamauchi T, Kamon J, Waki H. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 07: 941-946.
    CrossrefPubMedGoogle Scholar
  • 21 Pettersson AT, Mejhert N, Jernas M. et al. Twist1 in human white adipose tissue and obesity. J Clin Endocrinol Metab. 2011; 96: 133-141.
    CrossrefPubMedGoogle Scholar
  • 22 Westerbacka J, Yki-Jarvinen H, Turpeinen A. et al. Inhibition of platelet-collagen interaction: An in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002; 22: 167-172.
    CrossrefPubMedGoogle Scholar
  • 23 Fish RJ, Neerman-Arbez M. Fibrinogen gene regulation. Thromb Haemost 2012; 108: 419-426.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Souri M, Mokuda S, Inanami H. et al. Non-autoimmune combined factor XIII A and B subunit deficiencies in rheumatoid arthritis patients treated with anti-interleukin-6 receptor monoclonal antibody (tocilizumab). Thromb Res 2016; 140: 100-105.
    CrossrefPubMedGoogle Scholar
  • 25 Stirling D, Hannant WA, Ludlam CA. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6. Thromb Haemost 1998; 79: 74-78.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Matthews DR, Hosker JP, Rudenski AS. et al. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.
    CrossrefPubMedGoogle Scholar
  • 27 DeFronzo RA, Matsuda M. Reduced time points to calculate the composite index. Diabetes Care 2010; 33: e93-0646.
    CrossrefPubMedGoogle Scholar
  • 28 Kotronen A, Peltonen M, Hakkarainen A. et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 2009; 137: 865-872.
    CrossrefPubMedGoogle Scholar
  • 29 Szczepaniak LS, Nurenberg P, Leonard D. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288: E462-468.
    CrossrefPubMedGoogle Scholar
  • 30 Hyysalo J, Mannisto VT, Zhou Y. et al. A population-based study on the prevalence of NASH using scores validated against liver histology. J Hepatol 2014; 60: 839-846.
    CrossrefPubMedGoogle Scholar
  • 31 Brunt EM, Janney CG, Di Bisceglie AM. et al. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94: 2467-2474.
    CrossrefPubMedGoogle Scholar
  • 32 Petaja EM, Yki-Jarvinen H. Definitions of normal liver fat and the association of insulin sensitivity with acquired and genetic NAFLD-A systematic review. Int J Mol Sci 2016;. Epub ahead of print.
    PubMedGoogle Scholar
  • 33 Yki-Jarvinen H, Nikkila EA, Kubo K, Foley JE. Assay of glucose transport in human fat cells obtained by needle biopsy. Diabetologia 1986; 29: 287-290.
    CrossrefPubMedGoogle Scholar
  • 34 Meade TW, Cooper JA, Stirling Y. et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994; 88: 601-607.
    CrossrefPubMedGoogle Scholar
  • 35 de Lange M, Snieder H, Ariens RA. et al. The relation between insulin resistance and hemostasis: Pleiotropic genes and common environment. Twin Res 2003; 06: 152-161.
    CrossrefPubMedGoogle Scholar
  • 36 Luxembourg B, Schmitt J, Humpich M. et al. Cardiovascular risk factors in idiopathic compared to risk-associated venous thromboembolism: A focus on fibrinogen, factor VIII, and high-sensitivity C-reactive protein (hs-CRP). Thromb Haemost 2009; 102: 668-675.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Begbie M, Notley C, Tinlin S. et al. The factor VIII acute phase response requires the participation of NFkappaB and C/EBP. Thromb Haemost 2000; 84: 216-222.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Liaskou E, Wilson DV, Oo YH. Innate immune cells in liver inflammation. Mediators Inflamm 2012; 2012: 949157.
    PubMedGoogle Scholar
  • 39 Tissue expression of F9. Available at: http://www.proteinatlas.org/ENSG00000101981-F9/tissue Accessed June 23, 2016.
    PubMed
  • 40 Tissue expression of F11. Available at: http://www.proteinatlas.org/ENSG00000088926-F11/tissue Accessed June 23, 2016.
    PubMed
  • 41 Natali A, Toschi E, Baldeweg S. et al. Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. Diabetes 2006; 55: 1133-1140.
    CrossrefPubMedGoogle Scholar
  • 42 Wannamethee SG, Whincup PH, Rumley A, Lowe GD. Inter-relationships of interleukin-6, cardiovascular risk factors and the metabolic syndrome among older men. J Thromb Haemost 2007; 05: 1637-1643.
    CrossrefPubMedGoogle Scholar
  • 43 Kaye SM, Pietilainen KH, Kotronen A. et al. Obesity-related derangements of coagulation and fibrinolysis: A study of obesity-discordant monozygotic twin pairs. Obesity 2012; 20: 88-94.
    CrossrefPubMedGoogle Scholar
  • 44 Funnell AP, Crossley M. Hemophilia B leyden and once mysterious cis-regulatory mutations. Trends Genet 2014; 30: 18-23.
    CrossrefPubMedGoogle Scholar
  • 45 Safdar H, Cheung KL, Vos HL. et al. Modulation of mouse coagulation gene transcription following acute in vivo delivery of synthetic small interfering RNAs targeting HNF4alpha and C/EBPalpha. PLoS One 2012; 07: e38104.
    CrossrefPubMedGoogle Scholar
  • 46 Tissue expression of F13B. Available at: http://www.proteinatlas.org/ENSG00000143278-F13B/tissue Accessed June 23, 2016.
    PubMed
  • 47 Wolpl A, Lattke H, Board PG. et al. Coagulation factor XIII A and B subunits in bone marrow and liver transplantation. Transplantation 1987; 43: 151-153.
    CrossrefPubMedGoogle Scholar
  • 48 Cordell PA, Kile BT, Standeven KF. et al. Association of coagulation factor XIII-A with golgi proteins within monocyte-macrophages: Implications for subcellular trafficking and secretion. Blood 2010; 115: 2674-2681.
    CrossrefPubMedGoogle Scholar
  • 49 Owren PA. Thrombotest. A new method for controlling anticoagulant therapy. Lancet 1959; 02: 754-758.
    PubMedGoogle Scholar
  • 50 Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis 1999; 144: 273-283.
    CrossrefPubMedGoogle Scholar