The enzyme PLPP2 helps the mouse liver regenerate after acute injury
The enzyme PLPP2 helps the mouse liver regenerate after acute injury
On October 8, Signal Transduction and Targeted Therapy published a study of liver regeneration after acute injury. The authors conducted experiments in mice in which they deleted the gene encoding PLPP2 or increased its expression. Separately, in human liver biopsies, they observed an association between levels of this enzyme, cell division, and markers of injury.
The liver replaces lost tissue when its main cells, hepatocytes, resume dividing. Following toxic injury caused by acetaminophen, the authors measured proteins and metabolites in mouse livers over several days. Signs of injury predominated during the first 6–24 hours, while hepatocyte division and tissue regeneration increased by 48–96 hours. Levels of PLPP2 and phosphatidylethanolamine, PE, a lipid found in cell membranes, rose at the same time. The authors tested whether PLPP2 and PE contribute to regeneration or whether their levels simply rise as regeneration proceeds.
To test this, they deleted the Plpp2 gene specifically in hepatocytes. After acetaminophen exposure, these mice had larger areas of dead tissue, higher blood levels of ALT and AST, markers of liver injury, and fewer dividing cells. When the authors increased Plpp2 expression using an AAV vector that delivers an additional copy of the gene into cells, ALT and AST levels were closer to normal, areas of dead tissue were smaller, and more cells were dividing. Loss of Plpp2 also slowed regeneration after removal of 70% of the liver, toxic injury caused by carbon tetrachloride, and temporary interruption of blood flow.
The authors then examined the cellular mechanism. PLPP2 participates in a reaction that supports PE synthesis. PE attaches to the protein LC3B as the cell assembles a membrane vesicle to recycle damaged material. Rapamycin, which enhances this recycling process, partially reduced the effects of PLPP2 deficiency, while chloroquine, which blocks the process, eliminated the benefit of increased PLPP2 expression. PE binds to the protein PEBP1 and strengthens its interaction with GLI1, a regulator of genes involved in cell division. Within this complex, GLI1 binds less often to ITCH, a protein that marks GLI1 for degradation, allowing GLI1 to persist longer. The authors tested this sequence in experiments with proteins and cells, then related the findings to liver regeneration in mice.
In biopsies from 36 patients with drug-induced liver injury, higher PLPP2 levels were associated with more dividing cells and lower liver enzyme levels; 31 samples from patients with hepatic hemangioma served as a comparison. The measurements over time, the gene manipulation experiments, and the two pathways through which PE acts support a model in which membrane lipid metabolism helps the injured mouse liver restart cell division.