Towards Establishing L-Ornithine-L-Aspartate as a Potential Basic Medication for Metabolic Dysfunction-associated Steatotic Liver Disease

L-Ornithine and L-aspartate play key roles in detoxifying ammonium (NH3) and synthesizing proline and polyamines. Sufficiently synthesized de novo in healthy individuals, these amino acids have to be supplemented in, e.g., the metabolic dysfunction-associated steatotic liver disease (MASLD). Since the stable salt L-ornithine-L-aspartate (LOLA) enables the detoxification and excretion of NH3 by the urea cycle via activating carbamoyl phosphate synthetase 1, we investigated further potential therapeutic targets of LOLA. In primary hepatocytes from MASLD patients, the catabolism of branched-chain amino acids (BCAAs) decreased with disease severity. This could be partly reverted by LOLA via increasing the expression rates of the BCAA enzyme transcripts bcat2, bckdha and bckdk. Also, in both untreated HepG2 hepatoblastoma cells and HepG2-based models of steatosis, insulin resistance and metabolic syndrome, LOLA (i) reduced the release of NH3; (ii) beneficially modulated the expression of genes related to fatty acid import/transport (cd36, cpt1), synthesis (fasn, scd1, ACC1), and regulation (srbf1); (iii) reduced cellular ATP and acetyl-CoA; and (iv) favorably modulated the expression of master regulators/genes of energy balance/mitochondrial biogenesis (AMPK-α, pgc1α). Moreover, LOLA reconstituted the depolarized mitochondrial membrane potential ΔΨm without impairing mitochondrial integrity and/or inducing superoxide production. Most aforementioned effects were concentration-dependent at≤40 mM LOLA. Our results thus evidence for LOLA an impressive range of reconstituting effects on metabolic carriers and targets of catabolism and energy metabolism that are impaired in MASLD. These results warrant further investigation to establish LOLA as a safe, broadly efficacious and cost-effective basic medication for the ever-increasing MASLD pandemic.

Publication History

Article published online:
20 January 2025