Protective Role of Plasminogen Deficiency in Non-Alcoholic Fatty Liver Disease and Glucose Dysmetabolism

Obesity is global health problem with 40% of the world population being classified as overweight (BMI > 25) and 13% as obese (BMI > 30). Obesity drives chronic metabolic inflammation leading to metabolic syndrome, cardiovascular disease, fatty liver disease, Type II diabetes, and certain cancers. A documented clinical manifestation of obesity is perturbed and dysregulated hemostatic system leading to a procoagulant and anti-fibrinolytic state that ultimately results in an increased risk of thrombosis. Previous work suggested that clotting system components thrombin and fibrin engage in reciprocal mechanisms and contribute to the development of obesity. Specifically, we have shown that fibrin accumulates within obese adipose tissue and liver of obesity patients and mice challenged with a high fat diet (HFD) and colocalizes with macrophages, a key driver of inflammation in obesity. Despite the fact that obesity is known to be linked to an impaired fibrinolytic system, a potential functional contribution of fibrinolytic proteases to the development of obesity and associated downstream diseases has been understudied. Here, we tested the hypothesis that elimination of the fibrinolytic protease plasminogen would increase HFD-driven fibrin deposition and exacerbate macrophage accumulation and subsequent weight gain and obesity-associated pathologies. Contrary to our hypothesis, plasminogen-deficient (Plg-) mice gained as much weight as the Plg+ mice after 20 weeks on HFD. However, whereas the liver mass of HFD-challenged Plg+ mice was significantly higher than that of low fat diet (LFD)-fed mice, the livers of HFD-fed Plg- mice had a mass comparable to LFD-fed mice. HFD-fed Plg- mice had reduced hepatocellular damage, measured by plasma ALT activity, as well as reduced hepatosteatosis, measured by hepatic triglyceride content and liver histology, compared to HFD-fed Plg+ mice. Circulating cholesterol levels in HFD-fed Plg -/- mice were comparable to LFD-fed Plg- mice, while it was significantly elevated in HFD-fed Plg+ mice. While the epididymal white adipose tissue mass was higher in HFD-fed Plg- mice compared to HFD-fed Plg+ mice, the brown adipose tissue mass was comparable. However, there was an upregulation of uncoupling protein-1 (UCP-1) expression BAT of HFD-fed Plg- mice. Glucose clearance was more efficient in HFD-fed Plg- mice compared to HFD-fed Plg+ mice in a glucose tolerance test. Collectively, our data suggest that plasmin(ogen) contributes to HFD-induced fatty liver disease and glucose dysmetabolism. Disclosures No relevant conflicts of interest to declare.