Enzyme responsible for fatty acid may be IPF therapeutic target
Blocking FASN reduces signs of IPF in mice, study shows
Blocking fatty acid synthase (FASN), an enzyme responsible for fatty acid production in cells, reduced the signs of induced idiopathic pulmonary fibrosis (IPF) in mice, according to a study identifying the enzyme as a potential therapeutic target for the condition.
Experiments showed that FASN was elevated in lung scar tissue from IPF patients, and its inhibition suppressed the activation of fibroblast cells, which are the main drivers of tissue scarring during IPF progression.
“Targeting FASN inhibition in fibroblasts presents a promising therapeutic strategy for pulmonary fibrosis,” the researchers wrote. The study, “Fatty acid synthase inhibition alleviates lung fibrosis via β-catenin signal in fibroblasts,” was published in Life Science Alliance.
IPF is a chronic lung disease of unknown origin that causes the lungs to become stiff and scarred (fibrosis), making it difficult for a person to breathe. Symptoms include shortness of breath, a persistent dry cough, loss of appetite, weight loss, and fatigue.
Studies have suggested that FASN is expressed, or produced, at lower levels in lung tissues from IPF patients, particularly in certain cell types, including alveolar epithelial cells, which line the tiny air sacs in the lungs where gas exchange takes place, and immune macrophages. “However, the restructuring of lung tissue architecture in IPF may lead to varied alterations in FASN expression among different cell types within the lung tissues,” the researchers wrote.
FASN as therapeutic target
Fibroblasts, the most common cell type in connective tissue, are the main drivers of fibrosis during IPF progression. It’s widely accepted that the abnormal stimulation of multiple signaling pathways, including the Wnt/beta-catenin pathway, within lung fibroblasts contributes to the uncontrolled activation of these cells and the excessive deposition of scar tissue.
A research team in China assessed the expression of FASN in fibroblasts derived from fibrotic lung tissue and tested the impact of enzyme inhibition on fibrosis.
An examination of lung tissue sections from IPF patients revealed elevated FASN in fibroblasts in fibrotic lesions. In healthy tissue, the enzyme was mainly found in a type of alveolar epithelial cells. FASN was also found in fibrotic tissue from the lungs of mice with induced fibrosis.
When FASN protein expression was reduced in human fibroblast cells or the enzyme’s activity was suppressed by a pharmacological inhibitor called C75, pro-fibrotic activation was suppressed, and cells entered in a quiescent state, meaning they weren’t actively dividing. The production of collagen, the main protein found in scar tissue, was attenuated.
Experiments performed to understand the underlying mechanisms revealed that a protein called beta-catenin boosted FASN expression, while inhibiting FASN reduced beta-catenin expression.
Further work revealed that FASN inhibition promoted the production of two proteins, GSK3B and Axin1, that are negative regulators of the Wnt/beta-catenin pathway. FASN inhibition also stimulated autophagy, a process through which cells recycle damaged components, leading to beta-catenin’s degradation.
The researchers found that daily abdominal injections of C75 extended the lives of mice with induced fibrosis compared with those injected with saline. An examination of lung tissue showed that C75 significantly reduced the fibrotic area, acute lung injury scores, collagen deposition, and beta-catenin levels.
“Our findings indicate that FASN inhibition kept fibroblasts in a quiescent state … which effectively alleviated pulmonary fibrosis,” the researchers wrote. “These findings suggest that inhibiting FASN in fibroblasts may diminish the activity of the Wnt/[beta]-catenin signaling pathway, providing a potential therapeutic avenue for pulmonary fibrosis.”
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