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l-Ornithine-l-Aspartate (LOLA) Normalizes Metabolic Parameters in Models of Steatosis, Insulin Resistance and Metabolic Syndrome.
Pharmaceutics 2024 April 8
l-Ornithine- l-aspartate (LOLA) reduces toxic ammonium (NH3 ) plasma levels in hepatic encephalopathy. NH3 detoxification/excretion is achieved by its incorporation into urea and glutamine via activation of carbamoyl phosphate synthetase 1 (CSP1) by l-ornithine and stimulation of arginase by l-aspartate. We aimed at identifying additional molecular targets of LOLA as a potential treatment option for non-alcoholic fatty liver disease (NAFLD). In primary hepatocytes from NAFLD patients, urea cycle enzymes CSP1 and ornithine transcarbamylase (OTC) increase, while the catabolism of branched-chain amino acids (BCAAs) decreases with disease severity. In contrast, LOLA increased the expression rates of the BCAA enzyme transcripts bcat2 , bckdha , and bckdk . In untreated HepG2 hepatoblastoma cells and HepG2-based models of steatosis, insulin resistance, and metabolic syndrome (the latter for the first time established herein), LOLA reduced the release of NH3 ; beneficially modulated the expression of genes related to fatty acid import/transport ( cd36 , cpt1 ), synthesis ( fasn , scd1 , ACC1), and regulation ( srbf1 ); reduced cellular ATP and acetyl-CoA; and favorably modulated the expression of master regulators/genes of energy balance/mitochondrial biogenesis (AMPK-α, pgc1α ). Moreover, LOLA reconstituted the depolarized mitochondrial membrane potential, while retaining mitochondrial integrity and avoiding induction of superoxide production. Most effects were concentration-dependent at ≤40 mM LOLA. We demonstrate for l-ornithine-l-aspartate a broad range of reconstituting effects on metabolic carriers and targets of catabolism/energy metabolism impaired in NAFLD. These findings strongly advocate further investigations to establish LOLA as a safe, efficacious, and cost-effective basic medication for preventing and/or alleviating NAFLD.
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