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DiaComp Funded Abstracts

Program Application Abstract
Potential uses for bile-­acid micelles, as a vehicle for drug delivery, and (+)-­usnic acid in reversing Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Diabetes
Van, Justin   (Yale University)
Nonalcoholic fatty liver disease (NAFLD) has been implicated in the pathogenesis of type 2 diabetes and nonalcoholic steatohepatitis (NASH). Previous research by our lab has shown through a controlled-­release formulation of a mitochondrial protonophore (CRMP), that 2,4-­ dinitrophenol (DNP) can be exploited to reverse hypertriglyceridemia, hepatic steatosis, insulin resistance, and diabetes with a 500-­fold improvement in the therapeutic/toxic ratio over DNP. This study offered proof-­of-­concept in support of liver-­target liver mitochondrial uncoupling as a novel therapeutic target to treat type 2 diabetes and NAFLD/NASH. In this project we pursued two specific aims: 1) to explore naturally occurring protonophores that may reduce NAFLD with minimal off-­target effects and 2) to improve liver specificity for drug delivery in order to further minimize systemic toxicities associated with mitochondrial uncouplers. To identify new compounds that may reduce NAFLD, we first measured oxygen consumption rates in mouse hepatocytes challenged by a variety of natural protonophores. Interestingly, and similarly to what has been reported, we found that (+)-­usnic acid (UA) dose-­dependently increased oxygen consumption rate (OCR)—up to 75.4% basal levels with 30 µM UA. Next, to improve hepatic drug delivery and given entero-­hepatic circulation, bile-­acid micelles were explored as a vehicle for liver targeting. In vitro, DNP labeled micelles with 60% efficiency and showed increased uptake in HeLa cells (6-­fold increase over control). In vivo, compared to DNP only, DNP labeled micelles (Mi-­DNP) trended towards higher liver concentrations (p=0.07) with significantly lower skeletal muscle (p=0.02), kidney (p=0.00), and brown adipose tissue (p=0.02) concentrations. Taken together, our preliminary data indicate that (+)-­usnic acid and Mi-­DNP may be promising avenues to improve hepatic drug delivery, lower off-­target effects, and reverse nonalcoholic fatty liver disease, insulin resistance and diabetes.