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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK112119-02
Application #
9415444
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Silva, Corinne M
Project Start
2017-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tarling, Elizabeth J; Clifford, Bethan L; Cheng, Joan et al. (2017) RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. J Clin Invest 127:3741-3754
de Aguiar Vallim, Thomas Q; Lee, Elinor; Merriott, David J et al. (2017) ABCG1 regulates pulmonary surfactant metabolism in mice and men. J Lipid Res 58:941-954