Bile acids are the principal solid dissolved in bile. They play major roles in the formation of bile water, in the solubilization of bile lipids, and in the dispersion of the products of lipolysis in the gut lumen. During past years of grant support, we have studied bile acid metabolism in the developing organism. We have shown that such fundamental processes as bile acid synthesis, hepatic secretion, and intestinal absorption, are incompletely developed at birth and undergo maturation during the first weeks of life. In the grant period immediately preceding this application, we reexamined the bile acid constituents of human meconium. Meconium, the first feces of the newborn, contains the intestinal content of the fetus at birth, and, as such, is a record of intrauterine intestinal events. To our surprise, the bile acids of meconium proved to be a much more complex set than had previously been conceived. We identified several groups of short- chain bile acids, compounds which had largely been ignored in previous literature on bile acid metabolism. Although our analysis was limited to monohydroxylated bile acids (plus one dihydroxylated species), 10 to 15 previously unrecognized bile acids were identified. Certain of these were of major quantitative importance. Similar short-chain bile acids were identified in adult samples. In addition, preliminary studies suggested that glucuronidation was a major mechanism of short- chain bile acid metabolism, contrasting with the amino acid conjugation of conventional bile acids. During the projected grant period, problems raised by these findings will be pursued. We will broaden our identification of short-chain, and other atypical bile acids. Since the biological behavior of these compounds is largely unknown, we will further characterize their metabolism and turnover. We will prepare sets of bile acids with systematic variation in molecular configuration, and examine the influence of bile acid structure on function. We will perform a series of studies to begin to define the biosynthetic pathways of short-chain bile acid formation. Finally, we will further explore the role of glucuronidation in bile acid metabolism.
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