Transcriptome and Metabolome Profiling on the Potential of NMN/NR Against NAFLD
Introduction
Disturbance in hepatic NAD+ metabolism has been manifested as a key factor in the initiation and progression of nonalcoholic fatty liver disease (NAFLD), one of the most common chronic liver disease worldwide. Therapeutic methods aiming to increase NAD+ level are promising for NAFLD treatment. Both NMN and NR can raise NAD+ level. This research is designed to decipher their impacts and underpinned mechanism upon NAFLD based on the transcriptome and metabolome profiling.
NMN vs. NR
Relative to NR, NMN has an added phosphate group. This added phosphate group makes NMN a larger molecule than NR. Even so, NMN can be transported into cells through specific transporters, such as Slc12a8. NR is intermediate product in the synthesis of NAD+, and NMN is the direct precursor of NAD+. Once inside cells, NMN can be converted to NAD+ under the catalysis of NMNATs, whereas NR needs to be first converted to NMN by NRKs before conversion to NAD+.
The efficacy of NMN and NR in alleviating NAFLD
In mice with high-fat diet (HFD)-induced NAFLD, NMN or NR is administered through daily oral gavage. It has been found that NMN and NR reduce body weight gain, improve glucose homeostasis, regulate plasma lipid levels, and ameliorate liver injury, oxidative stress and lipid accumulation in mice subjected to HFD feeding. Importantly, both NMN and NR alleviate the HFD-induced NAFLD in mice, as evidenced by the ameliorative hepatic steatosis, inflammation, and fibrosis.
The mechanism underlying NAD+ precursor-mediated NAFLD remission
Integrated transcriptome and metabolome analysis indicate that arachidonic acid metabolism and linoleic acid metabolism pathway are involved in NMN/NR-induced NAFLD amelioration. Specifically, NMN and NR reduce the saturated fatty acid (palmitic acid, stearate, and arachidic acid) content to protect mice from liver toxicity, alter the arachidonic acid metabolism to regulate immune and inflammatory responses, and restore the decreased polyunsaturated fatty acid (linoleic acid and eicosapentaenoic acid) content in the liver of NAFLD mice.
Notably, Mup gene cluster, which can regulate lipid and energy metabolism, may function as a potential target for NMN and NR in the treatment of hepatic lipid accumulation. Furthermore, the CYP450 enzymes might be involved in NMN/NR-mediated arachidonic acid metabolism regulation.
Notably, Mup gene cluster, which can regulate lipid and energy metabolism, may function as a potential target for NMN and NR in the treatment of hepatic lipid accumulation. Furthermore, the CYP450 enzymes might be involved in NMN/NR-mediated arachidonic acid metabolism regulation.
Conclusion
Both NMN and NR administration significantly modify the hepatic lipid composition via Mup gene cluster, and alter linoleic acid metabolism and arachidonic acid metabolism pathways via CYP450 enzymes, which might mediate NAD+ administration-induced NAFLD remission.
Reference
Zhang J, Chen F. Integrated transcriptome and metabolome study reveal the therapeutic effects of nicotinamide riboside and nicotinamide mononucleotide on nonalcoholic fatty liver disease. Biomed Pharmacother. Published online May 9, 2024. doi:10.1016/j.biopha.2024.116701
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