fibrin and Weight-Gain

We examined the link between gestational biomarkers and breast cancer in 9169 daughters born into the Child Health and Development Studies from 1959 to 1967. We identified 137 breast cancer cases diagnosed by age 52 as of 2012. Markers of increased risk included higher placental volume and rapid 2nd trimester gestational weight gain. Protective markers were placental hemorrhage and fibrin deposition, indicators of resistance to placental trophoblast invasion. Paradoxically, higher ponderal index at birth was protective suggesting that fetal and placental pathways to breast cancer are multiple and distinct. Results link placental and fetal phenotypes to breast cancer, characterizing some as restrictive and others as permissive markers of tumor development. We found new biomarkers of breast cancer risk that can be mined to discover 'omic correlates in the pregnancy exposome using archived and contemporary pregnancy samples. This line of investigation may discover new pathways to risk and new opportunities for prevention.

Topics: Biomarkers; Breast Neoplasms; California; Child; Child Development; Child Health; Female; Fetal Development; Fibrin; Hemorrhage; Humans; Nuclear Family; Phenotype; Placenta; Pregnancy; Pregnancy Trimester, Second; Risk Factors; Weight Gain

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