ATP Binding Cassette Transporters in Health and Disease

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ABSTRACT Metabolic and chronic liver diseases are among the leading causes of death in the US. The liver is a central hub that coordinately regulates the metabolism of many nutrients, including lipids. The liver does not store lipids in the long-term, and lipid accumulation in the liver results in different diseases. Triglyceride accumulation in the liver causes steatosis which can progress to non-alcoholic steatohepatitis (NASH), both part of the non-alcoholic fatty liver disease (NAFLD) spectrum. Accumulation of bile acids in the liver because of viral infections, alcohol use or more advanced liver damage causes cholestasis. Identification of the molecular mechanisms of specific disease-promoting pathways is an essential step before pathways can be safely targeted for disease prevention. Our studies will further the understanding of the role of peroxisomal ABCD transporters in the liver. We have used an unbiased systems biology approach to identify new players in the regulation of lipid metabolism in the liver. Through these methods, we identified the peroxisomal transporter ABCD3 as a novel regulator of hepatic lipid metabolism. Abcd3−/− mice are partially lethal and loss of ABCD3 in surviving animals alters the hepatic lipidome and results in hepatomegaly and profoundly reduced biliary bile acids. To study ABCD3 in vivo, we have developed and validated a novel AAV-CRISPR strategy to disrupt Abcd3 exclusively in the liver, allowing us to disrupt Abcd3 in adult wild-type mice in a temporal fashion to determine the sequelae of events leading to the defects observed after loss of ABCD3. Using these tools, we show that acute loss of hepatic ABCD3 in adult mice is sufficient to recapitulate the dramatic reduction in biliary bile acids. When fed a Western diet (WD), loss of hepatic ABCD3 results in liver lipid accumulation as well as elevated plasma liver enzymes and bile acids, all hallmarks of NASH. We have designed two specific aims; in Aim 1 we will test the hypothesis that ABCD3 deficiency results in cholestasis and NASH. In Aim 2, we will identify specific substrates for ABCD3 and test the hypothesis that peroxisomal lipid defects are pathogenic and key for the development of NASH. Our studies demonstrate that loss of ABCD3, which is lethal in humans, results in cholestasis and NASH in a setting of elevated lipid levels. Completion of these studies will further the understanding of the role of peroxisomal ABCD transporters in the liver, and implicate peroxisomal lipid metabolism as an important contributor in the pathogenesis of NASH.