Combined Metabolic Activators Decrease Liver Steatosis by Activating Mitochondrial Metabolism in Hamsters Fed with a High-Fat Diet

• Published in: Biomedicines Vol. 9; no. 10; p. 1440
• Main Authors: Yang, Hong, Mayneris-Perxachs, Jordi, Boqué, Noemí, Del Bas, Josep M, Arola, Lluís, Yuan, Meng, Türkez, Hasan, Uhlén, Mathias, Borén, Jan, Zhang, Cheng, Mardinoglu, Adil, Caimari, Antoni
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11-10-2021; MDPI
• Subjects: Acetylcysteine; acid oxidation; Amino acids; Antioxidants; Biochemistry & Molecular Biology; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; Carnitine; combined metabolic activators; Commodities; deficiency; Diet; Disease; Drug dosages; expression; Fatty acids; Fatty liver; Folic acid; Genomes; Glutathione; High fat diet; insulin-resistance; L-Carnitine; Laboratory animals; Liver; Liver diseases; Metabolism; Metabolites; Mitochondria; mitochondrial; mitochondrial metabolism; Molecular modelling; NAD; NAFLD; Nutrition research; obesity; Oxidation; Oxidative stress; peroxisome; Pharmacology & Pharmacy; protects; Research & Experimental Medicine; Serine; Steatosis; transcriptomics; vitamin-c; United Kingdom > UK; United States > US; Spain; transcriptomics; NAFLD; combined metabolic activators; mitochondrial metabolism
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines9101440

Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD
precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.