{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:21:16Z","timestamp":1791361276075,"version":"4.3.1"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,7]],"date-time":"2024-04-07T00:00:00Z","timestamp":1712448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merz Pharma GmbH &amp; Co. KGaA, Frankfurt\/Main, Germany"},{"name":"Wilhelm Laupitz Foundation, D\u00fcsseldorf, Germany"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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-\u03b1, pgc1\u03b1). Moreover, LOLA reconstituted the depolarized mitochondrial membrane potential, while retaining mitochondrial integrity and avoiding induction of superoxide production. Most effects were concentration-dependent at \u226440 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics16040506","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T10:11:55Z","timestamp":1712571115000},"page":"506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["l-Ornithine-l-Aspartate (LOLA) Normalizes Metabolic Parameters in Models of Steatosis, Insulin Resistance and Metabolic Syndrome"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6069-7899","authenticated-orcid":false,"given":"Ali","family":"Canbay","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University Hospital, Knappschaftskrankenhaus, Ruhr University Bochum, 44892 Bochum, Germany"},{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"G\u00f6tze","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital, Knappschaftskrankenhaus, Ruhr University Bochum, 44892 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozlem","family":"Kucukoglu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7201-0836","authenticated-orcid":false,"given":"S\u00f6nke","family":"Weinert","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6248-7086","authenticated-orcid":false,"given":"Roland S.","family":"Croner","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Vascular and Transplantation Surgery, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-6461","authenticated-orcid":false,"given":"Theodor","family":"Baars","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital, Knappschaftskrankenhaus, Ruhr University Bochum, 44892 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa K.","family":"\u00d6z\u00e7\u00fcr\u00fcmez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital, Knappschaftskrankenhaus, Ruhr University Bochum, 44892 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-8516","authenticated-orcid":false,"given":"Robert K.","family":"Gieseler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital, Knappschaftskrankenhaus, Ruhr University Bochum, 44892 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,7]]},"reference":[{"key":"ref_1","first-page":"490","article-title":"Physiological functions of l-ornithine and l-aspartate in the body and the efficacy of administration of l-ornithine-l-aspartate in conditions of relative deficiency","volume":"28","author":"Sikorska","year":"2010","journal-title":"Pol. 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