Insulin Regulation of Hepatic Function via Zone-Specific Transcriptional Programs

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Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions in our society, and yet our understanding of the pathogenesis of this disorder remains rudimentary 7. Clinical studies show a close correlation between insulin resistance and the development and progression of NAFLD 8,9. To understand mechanistically the changes in triglyceride, cholesterol, and bile acid metabolism that occur with the development of NAFLD, a clear understanding of how insulin regulates these processes is necessary. Until now, studies of insulin action in the liver have been done with the assumption that all hepatocytes are equivalent. This assumption was made out of practicality, as our ability to isolate and analyze different populations of hepatocytes individually was limited. Yet, hepatocytes clearly vary in terms of the metabolic functions they perform, and their susceptibility to different insults 10. For example, the perivenous hepatocytes are the predominant site of bile acid synthesis and the most common site of triglyceride accumulation in NAFLD 11,12. Here, we will determine how insulin modulates gene expression in the perivenous hepatocytes to maintain homeostasis. Our novel, unpublished preliminary data reveal a striking example of zone-specific transcriptional regulation by insulin. We find that insulin suppresses Cyp8b1 only in the perivenous hepatocytes. Cyp8b1 encodes the sole enzyme capable of catalyzing the 12a-hydroxylation of bile acids 13; 12a-hydroxylated bile acids increase hepatic cholesterol and promote the progression to non-alcoholic steatohepatitis (NASH) 14-16. In the absence of insulin, the de-repression of Cyp8b1 in the perivenous hepatocytes is associated with increased 12a- hydroxylated bile acids, increased hepatic cholesterol, and severe inflammation. The fact that NAFLD progression in humans is also associated with an increase in 12a-hydroxylated bile acids and hepatic cholesterol, and the fact that inflammation marks the development of non-alcoholic steatohepatitis, a more severe and progressive form of disease, highlight the importance of studying this pathway 17-19. Based on these and other preliminary data, we hypothesize that insulin modulates the activity of b-catenin, a master transcriptional regulator that is activated only in the perivenous hepatocytes 20, to maintain normal lipid homeostasis and prevent inflammation. To test this hypothesis, we aim to (1) define the insulin-regulated cellular transcriptional programs in the liver using single-nuclei sequencing; and (2) dissect the role of b-catenin in producing the transcriptional and physiological response to insulin. We expect that insulin can reprogram the perivenous hepatocytes by modulating b-catenin driven transcription, and that this is required for normal homeostasis. Such results may ultimately lead to the development of precise interventions that reverse the effects of insulin resistance in the perivenous hepatocytes, preventing NASH.