Insulin regulation of hepatic transport

PROJECT SUMMARY Transport of bile acids from blood through the liver into the bile is a fundamental part of the enterohepatic cycle. Efficient transhepatic transport prevents cytotoxic effects of bile acids, and is critical for human health. We have unexpectedly found that insulin, a hormone long known as a chief orchestrator of postprandial metabolism, promotes hepatic bile acid transport. We have now shown that this occurs in humans, mice, and sandwich cultured murine hepatocytes, a polarized in vitro model of hepatic transport. Moreover, we find that obese, insulin resistant humans and mice have impaired hepatic bile acid transport, and this can be reversed by weight loss. In this grant, we propose to determine the underlying biology of this pathway: Through which upstream signaling mechanisms does insulin regulate bile acid transport? Which distal mediators of bile acid transport are ultimately employed to carry out insulin’s effects? Which aspects of this pathway are disrupted in obesity/insulin resistance? Does this pathway affect all bile acids? Is the effect specific to bile acids, or does it broadly affect canalicular secretion? We will use gold-standard bile acid kinetics studies, hyperinsulinemic- euglycemic clamps, state-of-the-art mass spectrometry, unique sandwich cultured hepatocyte models, and tissue-specific knockout mice. Success of this work is expected to elucidate a fundamental effect of insulin on hepatic function and postprandial nutrient handling.