# Dysregulated cholesterol homeostasis, caused by lysosomal/autophagy dysfunction, mediates pancreatitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $354,816

## Abstract

Summary/Abstract
Acute pancreatitis (AP) is a disorder with significant morbidity and mortality that lacks treatments. The
lysosomal/autophagy pathway – a key catabolic mechanism by which cells eliminate damaged cytoplasmic
organelles – is impaired in both experimental and human pancreatitis. Further, genetic alterations specifically
targeting autophagy or lysosomes cause spontaneous pancreatitis in mice. These findings implicate impaired
lysosomal/autophagy pathways in initiating and driving pancreatitis. The mechanisms through which disordering
of these pathways causes the disease remain, however, unknown. Studies in other organs and disease models
showed a critical role for lysosomal/autophagy pathways in regulating cholesterol homeostasis, essential for cell
viability and function. Moreover, recent studies indicate that use of cholesterol-lowering drugs, statins, is
associated with lower incidence of AP and decreased mortality. However, there is little known about cholesterol
metabolism in the exocrine pancreas and its’ dysregulation in pancreatitis. The effects of statins and other
cholesterol-lowering drugs on acinar cell cholesterol homeostasis and AP responses have not been studied. We
here propose a novel hypothesis for the pathogenic mechanism of pancreatitis: that lysosomal/autophagy
dysfunction causes dysregulation of acinar cell cholesterol homeostasis, leading to mitochondrial oxidative stress
and pathologic responses of pancreatitis.
 Our preliminary results indicate that both preclinical models and human pancreatitis are associated with
profound dysregulation of cholesterol homeostasis in acinar cells, and that lysosomal/autophagy dysfunction
associated with AP plays a key mediatory role in these effects. They further show the role of cholesterol
dysregulation in disease severity, in particular mitochondrial oxidative stress and inflammation.
The hypothesis will be tested in three Specific Aims:
1). Investigate dysregulation of acinar cell cholesterol homeostasis in experimental and human pancreatitis and
its role in pancreatitis responses.
2). Determine the role of cholesterol dysregulation in pancreatitis caused by disrupted lysosomal/autophagy
pathways.
3). Examine the role of cholesterol dysregulation in mitochondrial oxidative stress leading to inflammation in
pancreatitis.
The proposed research is significant because it will establish cholesterol metabolism as a clinically relevant
modulator of pancreatitis severity and identify potential molecular targets, amenable for pharmacologic
intervention, to normalize cholesterol metabolism and thus reduce pancreatitis severity. In particular, we will
elucidate the mechanisms of the effects of statins and other cholesterol-modulating drugs on pancreatitis.

## Key facts

- **NIH application ID:** 10587086
- **Project number:** 1R01DK131493-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ANNA S. GUKOVSKAYA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $354,816
- **Award type:** 1
- **Project period:** 2023-04-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10587086

## Citation

> US National Institutes of Health, RePORTER application 10587086, Dysregulated cholesterol homeostasis, caused by lysosomal/autophagy dysfunction, mediates pancreatitis (1R01DK131493-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10587086. Licensed CC0.

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