# Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2020 · $170,759

## Abstract

Liver injury of different etiologies leads to a wound healing process involving activation of hepatic stellate cells
(HSCs). However, an ongoing hepatocyte injury and inflammation results in an uncontrolled activation and
proliferation of HSCs and development of hepatic fibrosis leading to cirrhosis and even hepatocellular cancer.
Despite the advances made, gaps remain in our understanding of the mechanisms involved in the process of
HSC transformation from quiescent to activated phenotype. Recently, we discovered that the
phosphodiesterase 4 (PDE4) subfamily of enzymes play a pathogenic role in the development of cholestatic
liver injury and fibrosis. Notably, PDE4s are not present in quiescent HSCs and are rapidly induced upon
activation in vitro. Further, the PDE4 specific inhibitor, rolipram, effectively attenuates αSMA, collagen
expression and accompanying morphological changes in HSCs. PDE4 is the largest sub-family among cAMP-
hydrolyzing PDEs, which tightly regulate the levels of cellular cAMP. cAMP, through its effector molecules
protein kinase A (PKA) and Exchange Protein directly Activated by cAMP (EPAC), has been shown to down-
regulate cytokine induced fibrogenic genes in non-hepatic cells. Hence, we hypothesize that induction of PDE4
expression and activity plays a causal role in HSC activation by decreasing cAMP-PKA/EPAC activities and
promoting fibrogenic signaling. We postulate that during HSC activation, promoter associated epigenetic
changes and post-translational modifications play a significant role in the regulation of PDE4 expression and
activity. We also postulate that PDE4 inhibition will restore PKA/EPAC activities and attenuate TGFβ-Smad
signaling through: (i) inactivation of relevant MAPKs; and (ii) de-repressing PPARγ leading to decreased
expression of αSMA and Col1A1. Importantly, inhibition of PDE4 activity may be a significant therapeutic
approach for liver fibrosis. The specific aims of this proposal are to: 1) Determine the role of PDE4 in the
regulation of fibrogenic signaling in HSCs; 2) Determine promoter-associated epigenetic modifications
contributing to the induction of PDE4 isoforms during HSC activation; and 3) Determine the post-translational
modifications (PTMs) relevant for PDE4 isoform function during HSC activation. Importantly, the results of this
COBRE-funded project will provide proof-of-principle and mechanistic rationale for in vivo translational studies
(R01) to examine PDE4 targeted strategies for prevention and treatment of hepatic fibrosis.

## Key facts

- **NIH application ID:** 9904707
- **Project number:** 5P20GM113226-05
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Leila Gobejishvili
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $170,759
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904707

## Citation

> US National Institutes of Health, RePORTER application 9904707, Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling (5P20GM113226-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9904707. Licensed CC0.

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