Metabolic syndrome is a constellation of diseases that can encompass heart disease, obesity, diabetes, fatty liver disease and dyslipidemia. Bile acids are metabolites of cholesterol that can affect critical pathways involved in maintaining homeostasis in pathways that are dysregulated in metabolic disease. Bile acids are both detergents that help lipid absorption and signaling molecules that activate the nuclear receptor FXR. A number of current pharmacologic agents targeting FXR are currently being evaluated clinically. The success of FXR agonists as therapeutic agents requires a deep understanding of the molecular pathways regulated by FXR, many of which remain unknown. Here, we identify a novel mechanism whereby FXR regulates gene expression via a post-transcriptional mechanism. We identify a family of FXR-regulated RNA binding proteins (RBPs) that target specific mRNAs and are important in metabolism. More specifically, we show that these RBPs regulate bile acid synthesis and metabolism.
In Specific Aim 1, we will determine whether gain of function of each the RBPs will alter bile acid homeostasis in mice. Using a complimentary in vitro approach, we will determine whether this mechanism is conserved in a human context.
In Specific Aim 2, we will use our tissue-specific knockout mouse models to determine whether loss of function of these RNA binding proteins either alone or in combination results in abnormal regulation of bile acid synthesis and metabolism. Our preliminary data demonstrate that loss of one of the RBP family members in the liver causes a defect in bile acid metabolism. We will also determine the molecular targets of these RBPs in the liver. Together, our studies will challenge the current paradigm for how bile acid metabolism is thought to be regulated, and identify a novel molecular mechanism for how FXR is thought to maintain bile acid homeostasis.
Obesity, diabetes and heart disease, which are characterized by metabolic dysfunction, affects one third of adults in the US and creates a significant burden to the national health system. Bile acids and FXR signaling are important molecules that regulate several metabolic pathways that are dysregulated in disease states. The discovery that FXR regulates metabolism through a post-transcriptional mechanism will advance our fundamental understanding of physiologic processes, and may reveal novel opportunities for therapeutic intervention.
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