Comments from the Award Winners

On receiving the Best Oral Award Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo Ryutaro Tamura

　Thank you very much for the prestigious Best Oral Award at the 37th Annual Meeting of the Japanese Pharmacokinetics Society. I would like to express my sincere gratitude to the selection committee members and all the people involved in the Japanese Pharmacokinetics Society.

　Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a pediatric intractable liver disease caused by a genetic abnormality of ATP8B1, which encodes a phospholipid flippase. The pathogenesis of the disease is unknown, and patients develop biliary stasis cirrhosis by puberty. Liver transplantation is the final treatment, but even liver transplantation cannot save the patient’s life because of graft dysfunction originating from steatohepatitis after liver transplantation. Therefore, there is no effective treatment for this disease, and it is recognized as the most serious liver disease occurring in childhood, and extrahepatic organs have been suggested to contribute to the pathogenesis of the disease.

　In this study, to clarify the role of ATP8B1 in extrahepatic tissues, we generated tissue-specific ATP8B1-deficient mice and conducted phenotypic observations. As a result, we confirmed that intestinal epithelial cell-specific ATP8B1-deficient mice exhibit steatohepatitis after liver transplantation, similar to PFIC1 patients. We also performed metabolomic analysis of plasma and liver to search for the cause of fatty hepatitis, and found that the mice were choline-deficient. It is widely known that choline deficiency induces fatty hepatitis. Therefore, we fed the mice a choline-supplemented diet, and the fatty hepatitis recovered. These results suggest that the cause of fatty hepatitis in these mice is choline deficiency in vivo.

　The source of choline in vivo is derived from intestinal absorption of degradation products of phosphatidylcholine contained in the diet. Since ATP8B1 acts as a phospholipid flippase in cell membranes, I hypothesized that this molecule is responsible for the supply of choline to the body via the absorption of lysophosphatidylcholine (LPC) in intestinal epithelial cells. We conducted toxicity and transport studies and obtained results suggesting that LPC is a substrate for ATP8B1.

　These results suggest that ATP8B1 deficiency in intestinal epithelial cells induces choline deficiency due to LPC malabsorption, which in turn leads to steatohepatitis. We will continue our research to develop a treatment for PFIC1, encouraged by this award.