# Feedback Regulation of Fatty Acid and Triglyceride Synthesis by Polyunsaturated Fatty Acids (PUFAs)

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $653,745

## Abstract

Disorders associated with obesity represent some of the biggest medical challenges of this century.
These disorders encompass hypertriglyceridemia, cardiovascular disease, nonalcoholic fatty liver disease
(NAFLD), and diabetes. We have shown in animal models with insulin resistance that hypertriglyceridemia and
NAFLD share the same underlying molecular alteration: elevated nuclear SREBP-1c, which leads to increased
synthesis of fatty acids and triglycerides in the liver.
 Two SREBP isoforms exist in most organs, SREBP-1c and SREBP-2. Remarkably, feedback inhibition
of cholesterol synthesis and feedback inhibition of fatty acid synthesis are mediated by inhibition of the
proteolytic processing of SREBP-2 and SREBP-1c, respectively. Here, our goal is to delineate the molecular
mechanism by which polyunsaturated fatty acids (PUFAs) mediate the feedback suppression of fatty acid
synthesis by inhibiting the activation of SREBP-1.
 AIM 1 will examine a fundamental unanswered question in regulation of lipogenesis, namely, how is
SREBP-1c processing regulated independently from SREBP-2 despite using the same molecular machinery?
These studies will define the specific region of SREBP-1 that is responsible for mediating PUFA inhibition of
SREBP-1 cleavage and activation. We will use biochemical purification and somatic cell genetics to identify a
putative protein that binds PUFAs and interacts with SREBP-1, but not SREBP-2, to prevent cleavage and
activation. We will also define how PUFAs alter the membrane lipid composition of the endoplasmic reticulum
and how these changes prevent SREBP-1 cleavage.
 AIM 2 will investigate a recently discovered protein, Ubxd8, that binds and senses unsaturated fatty
acids. We will determine whether PUFAs inactivate Ubxd8 in mouse livers and elucidate its role in regulating
SREBP-1c processing in vivo.
 AIM 3 will explore why inhibiting the first committed enzyme in fatty acid synthesis (acetyl-CoA
carboxylase) prevents the development of fatty liver, even though this inhibition leads to activation of SREBP-
1c and hypertriglyceridemia.
 At its completion, RP 3 will elucidate new mechanisms that regulate SREBP activity and fatty acid
synthesis in liver, thereby providing new therapeutic opportunities for treatment of hypertriglyceridemia and
NAFLD.
 C/PPG 2015 – RP3 – 30-line Summary

## Key facts

- **NIH application ID:** 9940760
- **Project number:** 5P01HL020948-44
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JAY D. HORTON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $653,745
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940760

## Citation

> US National Institutes of Health, RePORTER application 9940760, Feedback Regulation of Fatty Acid and Triglyceride Synthesis by Polyunsaturated Fatty Acids (PUFAs) (5P01HL020948-44). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940760. Licensed CC0.

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