Liver function from Y to Z: The guidance of William Jakoby

In the 1960s, my lab was interested in understanding how bilirubin and other organic anions are transferred from the plasma through the liver cell and into the bile. We performed gel filtration of liver supernatants and identified two protein fractions, designated Y and Z, which bound organic anions including bilirubin, and thus we proposed that they were involved in hepatic uptake of organic anions from plasma. Subsequently, the Y and Z proteins responsible for this binding activity were purified, cloned, and sequenced. With Bill Jakoby, we identified Y protein as a member of the glutathione S-transferase (GST) protein family. In separate studies, Z was found to be a member of the fatty acid-binding protein (FABP) family. These proteins have since been shown to have additional surprising roles, but understanding of their full role in physiology and disease has not yet been achieved. In the 1960s, bilirubin metabolism was a "hot" topic. Along with other groups, my lab was studying various forms of inheritable jaundice in an effort to dissect the mechanism of bilirubin's transfer from plasma into the hepatocyte and its role in intracellular metabolism and biliary secretion. These processes were eventually identified and found to be related to the basic mechanisms whereby the liver handles many anionic drugs, metabolites, and hormones. Because the mechanism of hepatic uptake of bilirubin was unknown, A.J. Levi, Z. Gatmaitan, and I took advantage of advances in gel permeation chromatography to study this process. In 1969, we described two hepatic cytoplasmic protein fractions, designated Y and Z, that bound bilirubin and various organic anionic dyes in vivo and in vitro and, based on tissue distribution, abundance, and effects of genetic and pharmacologic models, were proposed to participate in organic anion uptake (Levi et al., 1969) [1]. In the decades since then, the Y and Z proteins have been identified as members of large protein families that were cloned and sequenced. Several surprising functions emerged, whereas others are proposed based on binding properties. Many challenges remain in understanding the full role of these proteins in physiology and disease.