Fatty acid transport proteins mediate fatty acid uptake in vivo and play a role in the development of metabolic diseases

The prevalence of obesity and diet-related diseases is widespread and increasing. Fatty acids have vital biological functions in the body, but can become pathophysiological in many contexts. It is well established that fatty acid uptake into cells is a regulated process mediated by membrane-bound fatty acid transporters. Gain- and loss-of-function studies of fatty acid transport proteins (FATPs) have demonstrated the essential role of fatty acid transporters in maintaining normal fatty acid metabolism and have also indicated that these proteins are involved in the development of diet-related diseases. We do not fully understand the physiological roles of each FATP in every metabolic context. The work presented here focuses on FATP1 and FATP6 activity in the heart and endocrine pancreas, particularly in the context of diabetes./nIn Chapter 1, the creation of a FATP6 knockout mouse model that we utilized to study FATP6 activity and function is reported. We found that FATP6 mediated fatty acid uptake in vivo and was specifically responsible for fatty acid availability in the heart. Deletion of FATP6 resulted in reduced cardiac lipid levels, cardiac dilation, reduced systolic function, and elevated rates of apoptosis in cardiomyocytes. This phenotype was rescued by high-fat diet feeding. While the location and mechanism of FATP6 activity have not been fully defined, we hypothesize that lack of FATP6 expression leads to reduced cardiac fatty acid utilization, which in turn leads to reduced cardiac function./nIn Chapter 2, our efforts to determine the role of FATP1 and FATP6 in the development of diabetic cardiomyopathy are described. Diabetic cardiomyopathy is a heart condition characterized by enhanced fatty acid utilization. We induced diabetes in wild-type and FATP1 and FATP6 knockout mice by feeding them a high-fat diet and injecting them with two low-doses of streptozotocin. This protocol produced hyperglycemia but did not result in a robust model of diabetic cardiomyopathy. Due to the lack of a strong phenotype in the heart, we did not detect significant differences in cardiac metabolism or function with deletion of FATP1 or FATP6./nIn Chapter 3, a novel role for FATPs in the endocrine pancreas is presented. FATPs are differentially expressed in pancreatic islets, with FATP1 localizing to beta cells. We used islets from FATP1 knockout mice to analyze how FATP1 expression affected the susceptibility of beta cells to lipotoxicity. Deletion of FATP1 protected beta cells from palmitate-induced apoptosis, despite normal levels of fatty acid uptake and palmitate-induced ER stress in FATP1 knockout islets. Although the mechanism explaining this outcome is not clear, beta cells from FATP1 knockout mice may differentially store neutral lipid and this may make the cells less susceptible to palmitate-induced cell death./nIn Chapter 4, our attempts to characterize small molecule inhibitors of FATPs are portrayed. We tested the ability of two classes of potential FATP inhibitors to reduce FATP activity in FATP-overexpressing cells and in cells that endogenously express FATPs. Phospholipid-based inhibitors did not reduce FATP-mediated fatty acid uptake at feasible concentrations. A dihydropyrimidone-based inhibitor effectively reduced FATP1- and FATP4-mediated fatty acid uptake in cell models overexpressing these proteins but did not affect endogenous FATP1 or FATP4 activity in other cell models./nTaken together, these results contribute to the growing body of evidence that establishes a role for FATPs in fatty acid transport in the body as well as in the development of diet-related diseases. Specifically, this work shows novel roles for FATP6 in cardiac metabolism and function and FATP1 in pancreatic beta cell metabolism and function. Clearly, FATPs are important regulators of metabolism, are implicated in metabolic disorders, and should be extensively studied as potential therapeutic targets.

Advisor: Stahl, Andreas