# Cholesterol-lowering drugs for treatment of pancreatitis: validation of a clinically significant novel therapeutic target and approach

> **NIH VA I21** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2023 · —

## Abstract

Pancreatitis is a common, potentially fatal, disease of the exocrine pancreas. There are 2 major forms of
pancreatitis: acute (AP), which usually produces an episode of temporary illness, and chronic (CP), associated
with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Pancreatitis is the
third most common reason for hospital admissions in those with GI disease and a heavy burden on the U.S.
healthcare system Major AP responses include inappropriate/intra-acinar activation of digestive enzymes,
increased serum level of amylase, neutrophil-driven inflammation, and acinar cell death. Key pathologic features
of CP are loss of acinar tissue, chronic inflammation and fibrosis, ultimately leading to the loss of exocrine and
endocrine pancreatic function. It is believed that CP results from repetitive subclinical or clinically evident bouts
of AP. Excessive alcohol consumption is a major risk factor for both forms of pancreatitis; other key risk factors
are smoking and age. The prevalence of these factors results in high pancreatitis incidence in Veterans as well
as in military personnel.
 The pathogenesis of pancreatitis remains obscure and no effective treatment is available, primarily because
we do not understand the underlying molecular and cellular mechanisms. Recent studies indicate that the
lysosomal/autophagy pathways – a key catabolic mechanism by which cells eliminate damaged or defective
cytoplasmic organelles and recycle their constituents for energy and biogenesis needs – are disrupted in
pancreatitis. Our recent study revealed that these pathways are critical for maintaining cholesterol homeostasis
in pancreas and their disordering results in acinar cell cholesterol overload. We further showed that the
cholesterol-lowering drug simvastatin alleviated experimental pancreatitis. Taken together, these findings
suggest that cholesterol metabolism is a clinically relevant modulator of pancreatitis severity. To validate the role
of cholesterol dysregulation in driving pancreatitis and establish cholesterol synthesis pathway as a therapeutic
target amenable to pharmacologic intervention in pancreatitis, we propose to examine the effects of cholesterol-
lowering drugs with different action mechanism, simvastatin and bempedoic acid (BemA), on disease severity in
several dissimilar mouse and ex-vivo (cellular) pancreatitis models. These preclinical AP and CP models reflect
the spectrum of disease severity and etiologies, such as excessive alcohol consumption, gallstones, and ERCP.
Statins came to medical use 30 years ago; BemA, which elicits fewer adverse effects than statins, was recently
approved by FDA for lowering cholesterol.
 The proposed studies will examine the effects of these drugs on pancreatic cholesterol levels and disease
severity using various regimens of drug administration in both preventive and therapeutic modes. The Specific
Aims will determine the effects of simvastatin and BemA on pancr...

## Key facts

- **NIH application ID:** 10585773
- **Project number:** 1I21BX006151-01
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** ANNA S. GUKOVSKAYA
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585773

## Citation

> US National Institutes of Health, RePORTER application 10585773, Cholesterol-lowering drugs for treatment of pancreatitis: validation of a clinically significant novel therapeutic target and approach (1I21BX006151-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10585773. Licensed CC0.

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