Subha Arthur, PhD
Mentor: Dr. Jung Han Kim
Obesity is increasingly being recognized as a growing epidemic around the world and has become one of the prime concerns of United States health care. More significantly, obesity is the prime reason for health disparity in the state of West Virginia. Obesity is characterized by accumulation of excess fat in the body, resulting in its related complications such as heart disease, stroke, type 2 diabetes, hypertension etc.
The primary source of fats is dietary. Absorption of dietary fats is in turn facilitated by intestinal bile acids. Bile acids are amphipathic molecules that are synthesized from cholesterol in the liver and secreted in bile into the small intestine where they facilitate solubilization and digestion of lipids. After aiding in lipid absorption, bile acids are reabsorbed in the distal intestine to be taken back into the enterohepatic circulation. Defective bile acid reabsorption at the distal intestine has been shown to reduce lipid and lipid soluble vitamin absorption resulting in malnutrition and related complications. Also, unabsorbed bile acids that enter colon cause increased colonic permeability and diarrhea. Therefore, it is essential for the body to maintain bile acid homeostasis and efficient enterohepatic circulation. In obesity, bile acid level has shown to be significantly increased in the intestine perhaps to enhance the absorption of dietary lipids. The intestinal transport of bile acids is mediated by apical sodium bile acid transporter ASBT present in the brush border membrane of the absorptive villus cells, in the terminal ileum. While bile acid is critical in the causation of obesity and its much morbidity, how ASBT may be regulated in obesity is not well understood.
Therefore, my current research focus is to decipher and understand how ASBT might be regulated in obesity. Physiological and molecular aspects of ASBT regulation will be understood using TALLYHO mice, a polygenic animal model for obesity. Better understanding of the regulation bile acid absorption that directly affects lipid absorption in obesity may result in novel and efficacious treatment modalities for this all-common condition with its multitude of morbidities.
Dysregulation of lipid homeostasis is a key characteristic of obesity, resulting in sequelae such as diabetes, cardiovascular diseases, fatty liver diseases, etc. Assimilation of lipids is entirely dependent on bile acid availability in the intestine. Bile acids are absorbed in the terminal ileal villus cell brush border membrane (BBM) via Na-bile acid-co-transporter (ASBT) requiring a favorable transcellular Na gradient provided by basolateral membrane (BLM) Na/K-ATPase. Novel preliminary findings suggest that in multiple species (including human), ASBT is upregulated secondary to Na/K-ATPase downregulation. Thus, the hypothesis of this project is that ASBT is uniquely regulated at the level of the cotransporter in the BBM, along with Na/K-ATPase in the BLM in intestinal cells during obesity. The observations of this study will result in novel data which will enhance our understanding of bile acid absorption, thereby, lipid assimilation dysregulation during obesity, and potentially lead to more efficacious treatment modalities.