Bile acids play critical physiological roles in lipid emulsification and in cholesterol elimination from the body. However, excessive hepatic accumulation of bile acids can lead to cholestatic liver injury. A decade ago, a major breakthrough in the bile acid research field occurred with the identification of the nuclear receptors responsible for feedback regulation of bile acid synthesis. Small heterodimer partner (SHP) was found to inhibit the expression of the rate limiting bile acid synthetic enzymes Cyp7a1 and Cyp8b1, as demonstrated by the first SHP-/- mice, which were generated by the PI. Our recent studies of hepatic SHP regulation have revealed the importance of a protein-protein interaction with B-cell lymphoma protein 2 (Bcl-2). Subsequent RNA-seq studies using our new liver Bcl-2 overexpressed mice identified a critical role for the long non-coding RNA (lncRNA) H19 in cholestatic liver fibrosis. H19 has been implicated in liver cancer, yet very little is know about its physiological and molecular action in liver diseases. The proposed investigation of the Bcl-2/SHP/H19 axis represents a pioneering study in integrating bile acid signaling with nuclear receptor regulation of H19 expression and function. The overall objective is to understand the role of lncRNA H19 in regulating bile acid homeostasis and the development of cholestatic liver fibrosis involving Bcl-2 and SHP. The central hypothesis is that Bcl-2 functions as a molecular switch to dictate H19 induction of cholestasis and liver fibrosis through SHP-mediated bile acid signaling.
Aim #1 : To uncover a critical pathophysiological role of Bcl- 2 in bile acid homeostasis;
Aim #2 : To reveal a crucial regulatory function of H19 in cholestatic liver fibrosis;
and Aim #3 : To define the signaling pathways that make H19 a bile acid sensor. The experiments proposed build on our long-standing experience in studying bile acid metabolism and regulation of gene expression, and the development and appropriate use of knockout and transgenic mouse models. Accordingly, our laboratory is uniquely poised to identify and validate a novel lncRNA H19 regulatory module in the bile acid signaling pathway. This is of great potential human relevance, because H19 expression is highly induced in various human fibrotic and cirrhotic liver specimens. Thus, the mechanistic insights elucidated through the proposed research may pave the way for the development of therapeutic strategies to specifically down regulate H19 and diminish H19 promotion of cholestatic fibrosis.
Disruption of bile acid homeostasis is closely associated with the development of cholestatic liver fibrosis and other chronic liver diseases in the United States. Long non-coding (lnc) RNAs are being increasingly recognized to have a profound impact in our understanding of disease pathobiology and leading to the emergence of new concepts underlying human diseases. This study will uncover for the first time the role of lncRNA in bile acid metabolism mediated by nuclear receptor signaling.
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