# Supplementation of L-aspartate corrects MASLD and MASH in mice by inhibiting platelet–hepatocyte interaction-mediated mitochondrial fragmentation via the ATP–P2X7–NEK7–DRP1 axis

## TL;DR

L-aspartate improves liver disease in mice by reducing platelet activity and improving mitochondrial health, suggesting it could be a new treatment for MASLD and MASH.

## Contribution

L-aspartate reverses MASLD and MASH by inhibiting platelet–hepatocyte interactions via the ATP–P2X7–NEK7–DRP1 axis.

## Key findings

- L-aspartate supplementation reversed MASLD and MASH in mice and improved hepatic mitochondrial quality.
- L-aspartate inhibited platelet activation and ATP secretion, blocking the P2X7–NEK7–DRP1 axis in hepatocytes.
- Blocking platelet activation with aspirin or P2X7 inhibitors also improved MASLD in mice.

## Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide prevalent metabolic disorder with increasing demands for therapeutic agents. l-aspartate is a nonessential amino acid that has great potential for curing liver disease. However, the therapeutic potential of l-aspartate against MASLD and its severe form metabolic dysfunction-associated steatohepatitis (MASH), as well as its metabolic regulation mode, are not well documented. Here we found that plasma and liver l-aspartate levels were decreased and negatively correlated with the severity of MASLD in mice and humans. l-aspartate supplementation in mice reversed the manifestations of both MASLD and MASH and these were correlated with improvements in hepatic mitochondrial quality and oxidation. The results of joint transcriptome and metabolomics analyses revealed that the metabolite cGMP and platelet activation were highly annotated after a single l-aspartate treatment. Notably, l-aspartate treatment increased cGMP levels in platelets and blocked platelet activation and aggregation, thereby suppressing activated platelet-derived ATP secretion and its mediated P2X7–NEK7–DRP1 axis hyperactivation in hepatocytes. Correspondingly, l-aspartate addition reversed the ATP-induced increases in oleatic acid-induced mitochondrial fragmentation and lipid accumulation. Interestingly, treatment with either the antiplatelet agent aspirin or the P2X7 inhibitor or NEK7 knockdown corrected oleatic acid + ATP-induced exacerbations of mitochondrial fragmentation and lipid accumulation in hepatocytes or ameliorated MASLD in mice. Notably, the l-aspartate increased cGMP levels in platelets was correlated with reductions in the plasma level of its inducers, including ADP and thrombin. These data together indicate that activated platelet-mediated mitochondrial fragmentation in hepatocytes is a pivotal driving force for MASLD and MASH. Blocking platelet activation underlies the therapeutic potential and metabolic regulation of l-aspartate against MASLD and MASH.

Hepatic l-aspartate levels are decreased in mice and humans with MASLD.Treating with l-aspartate efficiently reverses MASLD and MASH, alongside improvements in hepatic mitochondrial quality.l-aspartate inhibits platelet activation and its mediated release of the toxic substance ATP.ATP induces P2X7–NEK7–DRP1 axis hyperactivation in hepatocytes, contributing to mitochondrial fragmentation and lipid accumulation.l-aspartate is a promising anti-MASLD candidate that inhibits ATP-mediated platelet and hepatocyte interactions.

Hepatic l-aspartate levels are decreased in mice and humans with MASLD.

Treating with l-aspartate efficiently reverses MASLD and MASH, alongside improvements in hepatic mitochondrial quality.

l-aspartate inhibits platelet activation and its mediated release of the toxic substance ATP.

ATP induces P2X7–NEK7–DRP1 axis hyperactivation in hepatocytes, contributing to mitochondrial fragmentation and lipid accumulation.

l-aspartate is a promising anti-MASLD candidate that inhibits ATP-mediated platelet and hepatocyte interactions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition linked to obesity and diabetes. Currently, only one drug, resmetirom, is approved for treatment, but it has limited effectiveness. Researchers are exploring new treatments. Here researchers aimed to investigate the potential of l-aspartate, a nonessential amino acid, in treating MASLD. The study involved experiments on mice and analysis of human liver samples. The researchers found that l-aspartate levels were lower in the livers of both mice and humans with MASLD. They treated mice with l-aspartate and observed improvements in liver health and mitochondrial function. The study also showed that l-aspartate reduced platelet activation, which helped prevent liver damage. The results suggest that l-aspartate could be a promising treatment for MASLD by improving mitochondrial health and reducing harmful platelet activity.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.