# Novel Post-Transcriptional Regulators of Lipid Metabolism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $495,431

## Abstract

ABSTRACT
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.

## Key facts

- **NIH application ID:** 9857014
- **Project number:** 5R01DK112119-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Thomas A Vallim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $495,431
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857014

## Citation

> US National Institutes of Health, RePORTER application 9857014, Novel Post-Transcriptional Regulators of Lipid Metabolism (5R01DK112119-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857014. Licensed CC0.

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