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Review
. 2024 Jan 2;14(1):63.
doi: 10.3390/biom14010063.

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

Sri Jayanti  1   2 , Libor Vitek  3 , Camilla Dalla Verde  1   4 , John Paul Llido  1   4   5 , Caecilia Sukowati  1   2 , Claudio Tiribelli  1 , Silvia Gazzin  1
Affiliations
Review

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

Sri Jayanti et al. Biomolecules. .

Abstract

The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.

Keywords: Alzheimer’s disease; MAFLD; NRF2; Parkinson’s disease; bilirubin; cancer; heme-oxygenase; herbal medicine; neurodegeneration; nutraceuticals.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Bilirubin metabolism. CO: carbon monoxide, HMOX: heme oxygenase, ROS: reactive oxygen species, BLVR: biliverdin reductase.
Figure 2
Figure 2
Interconnections between heme metabolism and signaling pathways. Solid line: experimental evidence of a direct link. Dash lines: no experimental evidence of a direct action. Green lines: biliverdin action; yellow lines: bilirubin actinin; brown lines: CO action; blue lines: all other actions/connections. Yellow EFGR: epidermal growth factor receptor; NRF2: nuclear factor erythroid 2–related factor 2; ARE: antioxidant response element; CD: cluster of differentiation; HMOX: heme oxygenase; BV: biliverdin; BVLR: biliverdin reductase; BR: bilirubin; UGT1A1: UDP-glucuronosyltransferase 1A1; CAR: constitutive active/androstane receptor; PXR: pregnane X receptor; GR: glucocorticoid receptor; AhR: aryl hydrocarbon receptor; DRE/XRE: drought/xenobiotic-responsive elements; HNF1: hepatocyte nuclear factor 1α; PBREM: phenobarbital (PB)-responsive enhancer module; PPAR: peroxisome proliferator-activated receptor; SIRT: silent information regulator; MAPK: mitogen-activated protein kinase; JNK: Jun kinase; ERK: extracellular signal-regulated kinase; mTOR: mechanistic Target of Rapamycin; AMPK: AMP-activated protein kinase; AKT: protein kinase B; PKC: protein kinase C; TLR4: toll-Like receptor 4; NFkB: nuclear factor-κB; PIP: phosphatidylinositol biphosphate; PI3K: phosphatidylinositol-3-kinase; IRs: insulin receptor; S6K: protein S6 kinase; FGF: fibroblast growth factor; Glut1: glucose transporter type 1.
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Grants and funding

S.G., C.T. and C.D.V. have been funded by an internal grant from Fondazione Italiana Fegato (FIF). J.P.L. has been funded in part by an internal grant from Fondazione Italiana Fegato (FIF), in part by the Department of Science and Technology through the Philippine Council for Health Research and Development (DOST-PCHRD). S.J. has been funded by a 2023/2024 postdoctoral fellowship of Manajenen Talenta, Badan Riset dan Inovasi Nasional, Indonesia. C.S. has been funded in part by a 2023 grant of the Fondazione Veronesi, Milan, Italy, in part from the National Research and Innovation Agency of Indonesia. L.V. has been supported by grants MH CZ-DRO-VFN64165 from the Czech Ministry of Health, Cooperation Program, research area DIAG given by Charles University, and the project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES LX22NPO5104) funded by the European Union—Next Generation EU.
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