Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis

• Published in: Hepatology communications Vol. 8; no. 5
• Main Authors: Lyu, Junyan, Okada, Hikari, Sunagozaka, Hajime, Kawaguchi, Kazunori, Shimakami, Tetsuro, Nio, Kouki, Murai, Kazuhisa, Shirasaki, Takayoshi, Yoshida, Mika, Arai, Kuniaki, Yamashita, Tatsuya, Tanaka, Takuji, Harada, Kenichi, Takamura, Toshinari, Kaneko, Shuichi, Yamashita, Taro, Honda, Masao
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.05.2024
• Subjects: Original
• ISSN: 2471-254X; 2471-254X
• DOI: 10.1097/HC9.0000000000000425

Background: Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully. Methods: l-carnitine (2 g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated. Results: Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway. Conclusions: Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC.