Biliverdin and Bilirubin as Parallel Products of CO Formation

Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases

“…PPARγ activation of AMPK also led to inhibition of the mammalian target of rapamycin (mTOR signaling), an evolutionarily conserved nutrient-sensing protein kinase that regulates metabolism, aging processes, and overall life span [147,148], as well as dephosphorylation of a downstream factor, S6K [143]. Similar results on inhibition of S6K phosphorylation were also obtained in our study in human fibroblasts exposed to physiological concentrations of BR [14,149]. Interestingly, dysregulation of AMPK and mTOR hyperactivation was reported in BLVRA-deficient mice [84]; and in another study, BV inhibited TLR4 signaling in leukocytes and triggered phosphorylation of mTOR-specific targets, including Akt, PKC, and AMPK [89], suggesting the importance of BV and BR for modulation of these signaling pathways (Figure 2).…”

“…BV is not present in the circulation due to its rapid conversion to BR by biliverdin reductase (BLVR), a biologically potent enzyme with an important impact on cell function and metabolism [9]. Interestingly, BR has been shown to have even more versatile biological functions in all organs and compartments of the human body, including general antioxidant activities, immunosuppressive functions, and potent cell signaling properties [1,[10][11][12][13][14]. HMOX, the key enzyme responsible for the initiation of heme catabolism, has two isoforms (HMOX1, OMIM 141250; and HMOX2, OMIM 141251) [15,16].…”

“…mTOR Bilirubin [10,14] biliverdin [84] CO [85] Curcumin, quercetin, apigenin [86] Modulation of nutrient-sensing with impact on intermediary metabolism, aging processes, and overall life span.…”

“…As described in detail in our recent review [14], targeting the individual parts of the heme catabolic pathway represents an important way to increase tissue or systemic levels of BR.…”