Pathway Atlas

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated by metabolic stress and low-energy states.  AMPK inhibits energy-consuming anabolic pathways, such as protein synthesis, glycogen formation and cell growth, while stimulating energy utilization, glucose disposal and fatty acid oxidation. Because AMPK signaling inhibits inflammation while improving insulin sensitivity, endothelial function, and mitochondrial biogenesis, it is recognized as an attractive target for insulin sensitizing and cardioprotective agents.  Lifestyle interventions, such as caloric restriction and exercise, are well-established activators of this pathway. Various natural products, such as resveratrol, also stimulate AMPK and/or its downstream effectors.   
Oxidative stress, inflammation, infection, mitogens and toxins are major threats to cell and tissue health.  Chemopreventive phytochemicals, such as sulforaphane and polyphenols such as curcumin have demonstrated multimodal capacities to potentiate cellular defenses against these diverse threats.  Two major conduits of the protective effects of these compounds are the nuclear factor kappa B (NFκB) and nuclear transcription factor erythroid 2p45-related factor 2 (Nrf2) pathways.  Nuclear factor kappa B (NFκB) is a transcription factor comprised of two proteins, p50 and p65, that mediates pro-inflammatory responses at the genomic level.  Under basal circumstances, inactive NFκB is sequestered in the cytosol as part of the IκB kinase complex. Inductive stimuli, such as pro-inflammatory cytokines (e.g., TNFα), result in additional phosphorylation (tan circles) of IκBα. This enables proteasomal degradation of the sequestration complex, and translocation of p50 and p65 to the nucleus, where the dimer binds to response elements (K-boxes) located in the promoters of target genes.  Recruitment of coactivators and RNA polymerase induces transcription of target genes that include cytokines (TNFα), cyclooxygenase 2 (COX-2), anti-apoptotic proteins (Bcl2) and trophic factors that propagate pro-inflammatory and proliferative signals.  Polyphenols have been shown to inhibit multiple steps in this pathway, in addition to moderating growth factor signaling and other upstream events.  Arrows indicate activation, while diamond-pointed lines indicate inhibition. Nrf2 is a redox-sensing transcriptional regulator of endogenous antioxidant responses and detoxification.  Under homeostatic conditions, the Nrf2 transcription factor is restrained in the cytosol by Kelch-like ECH-associating protein 1 (Keap1). In the presence of oxidative, chemical, or electrophilic stress, Nrf2 translocates to the nucleus and heterodimerizes with Maf proteins to bind antioxidant response elements (AREs) in the promoters of protective genes encoding antioxidant proteins, phase II enzymes, glutathione biosynthetic enzymes.  Sulforaphane and curcumin activate Nrf2 by disrupting Keap1 binding.  
Flavonoids, a major class of polyphenols, occur widely in fruits, vegetables, tea, red wine, and various botanical extracts.  Examples include quercetin, hesperidin, anthocyanidins, catechins, and isoflavones.  Unconjugated flavonoids (aglycones) often possess sufficient lipophilicity to passively diffuse across the intestinal epithelial membranes into the portal blood.  However, in foods, flavonoids occur predominantly conjugated to a sugar (usually glucose), which increases polarity and limits passive uptake.  Some intact glycosides may be transported by membrane-associated transporters, such as sodium-glucose linked transporter 1 (SGLT1).  Alternatively, LPH (lactase phlorizin hydrolase) can hydrolyze the glycoside at the brush border to make passive diffusion possible.  A variety of flavonoids are substrates of ATP-binding cassette transporters, such as p-glycoprotein, which mediate efflux back into the lumen and limit the bioavailability of these compounds.  Intracellular glycosides are cleaved by cytosolic glucosidase (CG) and subject to metabolism by sulfotransferases (SULT) and/or UDP-glucuronosyltransferases (UGT), which produce sulfate and glucuronide conjugates, respectively.  These highly polar metabolites rely on membrane transporters, such as multidrug resistance associated proteins (MRPs) for basolateral transport into the circulation.  Phase II conjugates are also amenable to efflux.  Flavonoids and coinciding phytochemicals in foods can either utilize or inhibit transporters and efflux pumps, complicating research efforts to elucidate specific mechanisms of flavonoid uptake following ingestion of the complex mixtures found in foods.
Vitamin D status is a heritable trait with a complex genetic background involving the polymorphic steps shown. The influence of single nucleotide polymorphisms affecting these genes comprise a significant focus of nutritional genomics investigations.
The synthesis and metabolism of steroid hormones is regulated by a multiplicity of enzymes, some of which are modified by dietary and genetic influences. These flexible steps are indicated in bold colors.
Estrogen biosynthesis and metabolism are subject to variation based on a complex genetic background. Polymorphic steps in biosynthetic and transformation steps that have been actively investigated in humans are indicated in blue.
Caloric restriction and intermittent fasting increase cellular NAD+ levels. This increases SIRT1 activity and PGC1-alpha-mediated transcriptional coactivation of target genes involved in mitochondrial biogenesis. Amplification of mitochondrial number is one of the mechanisms by which dietary restriction ameliorates insulin resistance and related metabolic dysregulation.

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