fibrin and Fatty-Liver

Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (driven mostly by elevated levels of PAI-1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI-1 plays a causal role in the development of early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury.

Topics: Animals; Disease Progression; Ethanol; Fatty Liver; Fibrin; Fibrinolysis; Humans; Lipopolysaccharides; Lipoproteins, VLDL; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Mice; Plasminogen Activator Inhibitor 1

Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibγ390-396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte αMβ2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibγ390-396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients.

Topics: Adipose Tissue; Adiposity; Amino Acid Motifs; Animals; Blood Glucose; Body Composition; Body Weight; Coagulants; Dabigatran; Diet, High-Fat; Fatty Liver; Female; Fibrin; Genotype; Homozygote; Inflammation; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Thrombin; Weight Gain

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. Robust coagulation cascade activation is common in obese patients with NAFLD. We identified a critical temporal relationship between thrombin generation and the manifestation of hepatic steatosis, inflammation, and injury in C57BL/6J mice fed a high-fat diet (HFD) for 1, 2, and 3 months. Mice fed a HFD exhibited dramatic increases in hepatocellular injury and inflammation over time. Hepatic fibrin deposition preceded an increase in serum alanine aminotransferase, and the most dramatic changes in liver histopathology occurred in conjunction with a detectable increase in plasma thrombin-antithrombin levels at 3 months. To directly determine whether thrombin activity promotes NAFLD pathogenesis, mice were fed a HFD and simultaneously treated with the direct thrombin inhibitor dabigatran etexilate for 3 months. Notably, dabigatran treatment significantly reduced hepatic fibrin deposition, hepatic inflammation, hepatocellular injury, and steatosis in mice fed a HFD. Of interest, dabigatran treatment also significantly attenuated HFD-induced body weight gain. Gene expression analysis suggested that thrombin potentially drives NAFLD pathogenesis by altering the expression of genes associated with lipid metabolism and bile acid synthesis. Collectively, the results suggest that thrombin activity is central to HFD-induced body weight gain, liver injury, and inflammation and provide the proof-of-principle evidence that pharmacological thrombin inhibition could be effective in limiting NAFLD and associated pathologies.

Topics: Alanine Transaminase; Animals; Benzimidazoles; beta-Alanine; Bile Acids and Salts; Dabigatran; Diet, High-Fat; Fatty Liver; Fibrin; Gene Expression; Inflammation; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Thrombin; Weight Gain

Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations.

Topics: Animals; Arsenites; Chemical and Drug Induced Liver Injury; Dietary Fats; Disease Models, Animal; Extracellular Matrix; Fatty Liver; Fibrin; Inflammation; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Risk Factors; Sodium Compounds; Weight Gain

Liver biopsies of sixty patients with different forms of hepatitis and ten control subjects without hepatic disorders were examined by means of direct immunofluorescent methods for the HBsAg, immunoglobulins, fibrin and C3. The presence of fluorescent particles of HBsAg in the cytoplasm of hepatocytes were correlated with the presence of HBsAg in the serum. The fluorescence did not seem specific of histological stage of hepatitis. Immunoglobulins and fibrin were often demonstrated in hepatic sinusoids, especially in chronic aggressive hepatitis. In contrast, C3 is rarely observed.

Topics: Biopsy; Complement C3; Complement System Proteins; Cytoplasm; Epitopes; Fatty Liver; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Hepatitis; Hepatitis B Antigens; Humans; Immunoglobulins; Liver; Liver Cirrhosis; Liver Diseases; Renal Dialysis

Topics: Acute Disease; Adult; Aged; Alcoholism; alpha 1-Antitrypsin; Alpha-Globulins; Chronic Disease; Fatty Liver; Female; Fibrin; Fibrinogen; Fibrinolysis; Hepatitis; Humans; Liver Cirrhosis; Liver Cirrhosis, Biliary; Macroglobulins; Male; Middle Aged; Plasminogen

Topics: Acute Disease; Adult; Disseminated Intravascular Coagulation; Fatty Liver; Female; Fibrin; Gastrointestinal Hemorrhage; Humans; Jaundice; Liver; Maternal Mortality; Pregnancy; Pregnancy Complications; Time Factors

Topics: Animals; Aorta; Aortic Diseases; Blood Flow Velocity; Cell Membrane; Dietary Fats; Endothelium; Fatty Liver; Female; Fibrin; Mice; Microscopy, Electron; Organoids; Platelet Adhesiveness; Pregnancy; Thrombosis; Time Factors