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Lack of phosphoenolpyruvate carboxykinase 1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis

GSE313667 Mus musculus Expression profiling by high throughput sequencing 8 samples Submitted 2026/02/02 Platform GPL28457
Summary
Phosphoenolpyruvate carboxykinase (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic animals and people with fibrosis, correlating negatively correlated with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid cycle activity, but PCK1 overexpression reduces acetyl-CoA, limiting tricarboxylic acid cycle intermediates and ameliorating HSCs activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.
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Also filed as BioProject PRJNA1380498 and SRA study SRP654910. Searching any of these in the dataset finder brings you back here.

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