OC 28.4 - Protective Role of Plasminogen Deficiency in Non-Alcoholic Fatty Liver Disease and Glucose Dysmetabolism

Background: Obesity affects over 40% of Americans and predisposes individuals to metabolic syndrome, which is associated with increased risk of cardiovascular events. A documented clinical manifestation of obesity is a shift in the hemostatic system to a procoagulant and anti-fibrinolytic state with elevated fibrinogen, fibrin deposition in multiple tissues and suppressed plasmin(ogen) activation and plasmin activity. Whereas recent studies have documented a function contribution of fibrinogen to progression of obesity and metabolic syndrome, a potential role for plasminogen has remained largely undefined.

Aims: Determine the contribution of plasmin(ogen) itself to the development of obesity and associated disease sequelae.

Methods: The impact of plasminogen deficiency on high fat diet (HFD)-driven weight gain, metabolic inflammation, and obesity-associated pathologies was analyzed by challenging plasminogen-deficient (Plg-) and control (Plg+) mice with low-fat diet (LFD) or HFD for 20 weeks.

Results: Over the course of 20 weeks, Plg- mice gained as much weight as Plg+ mice on HFD, although the epididymal white adipose tissue of HFD-fed Plg- mice had a greater mass than that of HFD-fed Plg+ mice. In contrast, livers of HFD-challenged Plg+ mice were significantly larger than that of HFD-fed Plg- mice. HFD-fed Plg+ animals displayed a fatty liver disease phenotype characterized by histological evidence of steatosis, elevated triglyceride content, and hepatocellular injury (i.e., elevated plasma ALT). However, HFD-fed Plg- mice were protected from developing each of these pathologies. HFD-fed Plg+ mice also developed hypercholesterolemia, whereas cholesterol levels in Plg- mice were comparable to LFD-fed mice. Notably, whereas HFD-fed Plg+ mice showed evidence of diabetes as revealed by compromised glucose clearance, HFD-fed Plg- mice were partially protected.

Conclusion(s): Collectively, our data suggest that plasmin(ogen) contributes to HFD-induced fatty liver disease and glucose dysmetabolism, and that plasminogen deficiency imposes a state of metabolically healthy obesity.