Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis

by Selleckchem | Oct 25 2023

To identify metabolomic reprogramming in early hyperlipidemia, unbiased metabolome was screened in four tissues from ApoE-/- mice fed with high fat diet (HFD) for 3 weeks. 30, 122, 67, and 97 metabolites in the aorta, heart, liver, and plasma, respectively, were upregulated. 9 upregulated metabolites were uremic toxins, and 13 metabolites, including palmitate, promoted a trained immunity with increased syntheses of acetyl-CoA and cholesterol, increased S-adenosylhomocysteine (SAH) and hypomethylation and decreased glycolysis. The cross-omics analysis found upregulation of 11 metabolite synthetases in ApoE‾/‾ aorta, which promote ROS, cholesterol biosynthesis, and inflammation. Statistical correlation of 12 upregulated metabolites with 37 gene upregulations in ApoE‾/‾ aorta indicated 9 upregulated new metabolites to be proatherogenic. Antioxidant transcription factor NRF2-/- transcriptome analysis indicated that NRF2 suppresses trained immunity-metabolomic reprogramming. Our results have provided novel insights on metabolomic reprogramming in multiple tissues in early hyperlipidemia oriented toward three co-existed new types of trained immunity.

Comments:

The research you described focuses on identifying metabolomic reprogramming in early hyperlipidemia using an unbiased metabolome screening approach in ApoE-/- mice fed a high-fat diet for 3 weeks. The study examined four tissues: aorta, heart, liver, and plasma.

The results showed that a significant number of metabolites were upregulated in each tissue. Specifically, there were 30 upregulated metabolites in the aorta, 122 in the heart, 67 in the liver, and 97 in the plasma. Among these upregulated metabolites, nine were identified as uremic toxins, and 13 metabolites, including palmitate, were found to promote a type of immune response called trained immunity. This immune response was characterized by increased synthesis of acetyl-CoA and cholesterol, elevated levels of S-adenosylhomocysteine (SAH) leading to hypomethylation, and reduced glycolysis.

Further analysis through cross-omics techniques revealed the upregulation of 11 metabolite synthetases in the aorta of ApoE-/- mice. These synthetases were found to promote the generation of reactive oxygen species (ROS), cholesterol biosynthesis, and inflammation. Additionally, a statistical correlation analysis identified 12 upregulated metabolites that were linked to 37 gene upregulations in the ApoE-/- aorta. This correlation analysis suggested that nine of the upregulated metabolites could potentially contribute to the development of atherosclerosis, indicating their proatherogenic nature.

To explore the role of the antioxidant transcription factor NRF2, transcriptome analysis was performed on NRF2-/- mice. The findings indicated that NRF2 suppresses the metabolomic reprogramming associated with trained immunity. This suggests that NRF2 may play a role in modulating the effects of hyperlipidemia on the immune system and metabolic pathways.

In summary, this study provides novel insights into the metabolomic reprogramming that occurs in multiple tissues during early hyperlipidemia. The findings highlight the presence of three co-existing types of trained immunity and their association with metabolites, gene upregulation, and atherosclerosis-related processes. Additionally, the study implicates NRF2 as a potential regulator of trained immunity and metabolomic changes in hyperlipidemia.