# Lipid-Responsive E3 ubiquitin ligases in cholesterol metabolism and atheroscierosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $514,800

## Abstract

Abstract
 Elucidating new control mechanisms for cholesterol homeostasis that affect atherosclerosis will advance
our understanding of fundamental physiological processes and may suggest new opportunities for intervention
in human metabolic disease. We propose to define the mechanism of action and physiological function of two
new LXR-dependent regulatory circuits mediated by two novel E3 ubiquitin ligases. Molecular mechanisms
mediating crosstalk between the SREBP-2 and LXR pathways are poorly understood. Using an RNA
sequencing strategy to identify new LXR targets, we have uncovered two uncharacterized genes–Rnf145 and
Rnf186–that may mediate critical pathways for crosstalk between LXR and SREBP signaling. Rnf145 and
Rnf186 encode RING domain-containing proteins predicted to be E3 ubiquitin ligases; however, their
ubiquitination targets and biological function are unknown. Our preliminary data have revealed that both
RNF145 and RNF186 are previously unrecognized modulators of SREBP-2 signaling. Manipulation of Rnf145
and Rnf186 expression in mouse liver regulates SREBP-2-dependent gene expression and plasma cholesterol
levels by distinct but complementary mechanisms. Based on these findings, we propose a series of molecular,
cell biological and physiological studies to define the functions of RNF145 and RNF186 in cholesterol
homeostasis and their contribution to LXR-SREBP crosstalk. Aim 1 is to elucidate the function and mechanism
of action of RNF145 in lipid metabolism. Aim 2 is to elucidate the function and mechanism of action of RNF186
in lipid metabolism. Aim 3 is to determine the physiological importance of RNF145 and RNF186 for LXR-
SREBP crosstalk and atherosclerosis.

## Key facts

- **NIH application ID:** 9836871
- **Project number:** 5R01HL136618-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** PETER J TONTONOZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $514,800
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836871

## Citation

> US National Institutes of Health, RePORTER application 9836871, Lipid-Responsive E3 ubiquitin ligases in cholesterol metabolism and atheroscierosis (5R01HL136618-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836871. Licensed CC0.

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