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Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury.

ABSTRACT: Patients with chronic liver disease and cirrhosis have a dysregulated coagulation system and are prone to thrombosis. The basis for this hypercoagulable state is not completely understood. Tissue factor (TF) is the primary initiator of coagulation in vivo. Patients with cirrhosis have increased TF activity in white blood cells and circulating microparticles. The aim of our study was to determine the contribution of TF to the hypercoagulable state in a mouse model of chronic liver injury.We measured levels of TF activity in the liver, white blood cells and circulating microparticles, and a marker of activation of coagulation (thrombin-antithrombin complexes (TATc)) in the plasma of mice subjected to bile duct ligation for 12days. We used wild-type mice, mice with a global TF deficiency (low TF mice), and mice deficient for TF in either myeloid cells (TF(flox/flox),LysMCre mice) or in hepatocytes (TF(flox/flox),AlbCre).Wild-type mice with liver injury had increased levels of white blood cell, microparticle TF activity and TATc compared to sham mice. Low TF mice and mice lacking TF in hepatocytes had reduced levels of TF in the liver and in microparticles and exhibited reduced activation of coagulation without a change in liver fibrosis. In contrast, mice lacking TF in myeloid cells had reduced white blood cell TF but no change in microparticle TF activity or TATc.Hepatocyte TF activates coagulation in a mouse model of chronic liver injury. TF may contribute to the hypercoagulable state associated with chronic liver diseases in patients.

SUBMITTER: Rautou PE

PROVIDER: S-EPMC4691429 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury.

Rautou Pierre-Emmanuel PE Tatsumi Kohei K Antoniak Silvio S Owens A Phillip AP Sparkenbaugh Erica E Holle Lori A LA Wolberg Alisa S AS Kopec Anna K AK Pawlinski Rafal R Luyendyk James P JP Mackman Nigel N

Journal of hepatology 20150829 1

<h4>Background & aims</h4>Patients with chronic liver disease and cirrhosis have a dysregulated coagulation system and are prone to thrombosis. The basis for this hypercoagulable state is not completely understood. Tissue factor (TF) is the primary initiator of coagulation in vivo. Patients with cirrhosis have increased TF activity in white blood cells and circulating microparticles. The aim of our study was to determine the contribution of TF to the hypercoagulable state in a mouse model of chr ...[more]

PMID: 26325534

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Project description:BackgroundObstructive sleep apnea (OSA) is associated with the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing ? subunit of hypoxia inducible factor-1 (HIF-1), a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.MethodsWild-type mice and mice with hepatocyte-specific HIF-1? knockout (Hif1a-/-hep) were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2) or normoxia (16% O2) for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.ResultsWild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 ?g collagen/mg liver tissue, versus 1.23 ?g collagen/mg liver tissue, p = 0.03), which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.ConclusionsHepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver tissue hypoxia in hepatic steatosis. HIF-1 is necessary for collagen cross-linking in an in vitro model of fibrosis.

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Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury.

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Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury.

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