Molecular Physiology of Liver Fatty Acid Transporters

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DESCRIPTION (provided by applicant): Accumulation of hepatic lipids has been linked to the development of hepatic insulin resistance. Particularly, in obese individuals chronically elevated serum free fatty acids (FFA) and high insulin levels lead to increased FFA uptake by the liver and increased synthesis of lipids resulting in hepatic steatosis. Here we postulate that hepatic FATPs are multifunctional proteins facilitating both protein-mediated fatty acid uptake/activation as well as bile activation, linking hepatic fatty acid and sterol metabolism. We propose that inhibiting liver FATPs may alter inter-organ and intracellular lipid fluxes and therefore influence hepatic steatosis, insulin sensitivity, whole body glucose homeostasis, as well as bile related diseases such as cholelithiasis. We will demonstrate this multifunctional role in vitro and in vivo by determining the interdependence of transport and enzymatic activities of hepatic FATPs and by determining the mechanism by which inhibition of hepatic FATPs can improve hepatosteatosis and other hepatobiliary disorders as well as insulin resistance. To address the biological and therapeutical implications of suppression of hepatic FATPs in vivo, we have developed and implemented adeno-associated virus (AAV) mediated shRNA expression systems, genetic knockout approaches, and anti- sense oligo nucleotide (ASOs) based regiments which will be used to delineate the extend and mechanisms by which inhibition of hepatic FATPs can improve obesity related hepatobiliary disease and insulin sensitivity. Ultimately, our studies will demonstrate whether hepatic FATPs could represent novel targets for the treatment of obesity associated hepatobiliary diseases as well as diabetes.