Abstract
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.
Highlights
Hepatic steatosis (HS) is defined as the excessive accumulation of fat in the liver (>5.5% tissue weight), and it is the characteristic feature of non-alcoholic fatty liver disease (NAFLD) [1]
We found that fatty acid metabolism, catabolism of amino acids including branched-chain amino acids (BCAAs) and lysine, metabolism of amino acids, as well as signaling pathways in the regulation of insulin resistance and fatty acid oxidation (e.g., AMPK-signaling pathway) were significantly enriched with the down-regulated
We found that the hepatic expression of genes associated with fatty acid oxidation in peroxisome and mitochondria (SLC27A5, ABCD1, ACOT8, ACSM1, ACSM3, and ACSM5) were elevated in the liver of combined metabolic activators (CMA)-treated hamsters, which could be related to the supplementation of L-carnitine tartrate (LCT) and NR
Summary
Hepatic steatosis (HS) is defined as the excessive accumulation of fat in the liver (>5.5% tissue weight), and it is the characteristic feature of non-alcoholic fatty liver disease (NAFLD) [1]. NAFLD is a widespread metabolic disorder that can be considered a Biomedicines 2021, 9, 1440. Biomedicines 2021, 9, 1440 multifactorial disease and that refers to a group of conditions including HS and various degrees of liver inflammation, such as non-alcoholic steatohepatitis (NASH). NAFLD can progress to cirrhosis, and hepatocellular carcinoma (HCC), which are much more severe liver diseases [1,2,3]. Research in drug development for NAFLD is intense and advancing rapidly, there are still significant unmet challenges with no effective drug approved for this condition [4]. It is of paramount importance to find effective treatments against this disease and to elucidate the underlying mechanisms
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