# Regulation and consequences of hepatic lipid droplet catabolism

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $454,025

## Abstract

PROJECT SUMMARY
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is tightly linked to
numerous metabolic diseases. Lipid droplet (LDs) are the major storage organelles of intracellular
triacylglycerol (TAG) and, therefore, are the defining characteristic of NAFLD. In contrast to historical views of
LDs as simply inert forms of energy storage, recent studies have identified LDs as important organelles that
influences cellular function and signaling in addition to the regulation of TAG content and turnover. Given the
prevalence of NAFLD and its massive burden worldwide, understanding the mechanisms governing LD
metabolism is paramount if we aim to progress to effective dietary, lifestyle or pharmaceutical therapies
targeting NAFLD and its comorbidities. This application will build upon recent findings from our laboratory
regarding the role of adipose triglyceride lipase (ATGL) in liver energy metabolism. Our published and
preliminary data show that ATGL is a major hepatic lipase that promotes oxidation of hydrolyzed fatty acids
(FAs) and links cAMP/PKA signaling to sirtuin 1 (SIRT1)-mediated induction of PGC-1a and its transcriptional
binding partners (e.g. PPAR-a and FoxO1). Once activated in response to ATGL, SIRT1 promotes
autophagy/lipophagy, which in turn is responsible for bulk degradation of hepatic LDs and the subsequent
efflux of FAs. Based on this data, the objective of this proposal is to elucidate the physiological and
mechanistic regulation of lipophagy and trafficking of lysosome-derived FAs. We hypothesize that ATGL, via
intracellular trafficking of oleate, activates SIRT1 to control specific arms of lipophagy leading to LD catabolism
and lysosomal-mediated FA efflux. To test our hypothesis, we will conduct the following specific aims: 1) to
characterize the physiological regulation of and interplay between ATGL and lipophagy/FA efflux; 2) to define
the mechanism linking ATGL to SIRT1 signaling and lipophagy induction; and 3) to elucidate the regulation and
consequences of lysosomal-mediated FA efflux on hepatic energy metabolism. Aim 1 will employ cell, perfused
liver and mouse models to characterize how physiological factors regulate lipophagy. Aim 2 will use both cell
and mouse models to dissect out the signaling network linking ATGL to the regulation of autophagy/lipophagy
and FA efflux. Aim 3 will focus on lysosome fusion to the plasma membrane as a therapeutic target to increase
lipophagy. These studies are innovative in that they will answer novel questions about the regulation of LD
catabolism and signaling. This work is significant because it advances our understanding of the defining
characteristic of NAFLD (i.e. LDs), which will have a positive and sustained impact towards the goal of
preventing or treating NAFLD and related comorbidities.

## Key facts

- **NIH application ID:** 9968402
- **Project number:** 5R01DK114401-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Douglas G Mashek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,025
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-12-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968402

## Citation

> US National Institutes of Health, RePORTER application 9968402, Regulation and consequences of hepatic lipid droplet catabolism (5R01DK114401-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9968402. Licensed CC0.

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