Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Figure 1 Homocysteine metabolism. Homocysteine has three main metabolic fates: to be remethylated to methionine, to en-ter the cysteine biosynthetic pathway, and to be released into the extracellular medium. CBS, cystathionine -synthase; MS, methionine synthase; THF, tetrahydrofolate; MTHFR, 5, 10-methylenetetrahydrofolate reductase; BHMT, betaine-ho-mocysteine methyltransferase; DMG, dimethylglycine; MAT, methionine adenosyltransferase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine.

Figure 2 Cellular mechanisms by which homocysteine pro-motes cell injury. Homocysteine causes activation of necrosis factor-κB (NF-κB) and enhances production of cytokines (IL-1β, IL-6, and IL-8) resulting in inflammatory reactions, increases intracellular levels of superoxide anion causing oxidative stress, and induces endoplasmic reticulum (ER) stress by causing misfolding of proteins traversing the ER. Homocysteinyl-tRNA increases production of highly reactive derivative homocys-teine thiolactone which damages enzymes and DNA. IRE1, type 1 ER transmembrane protein kinase; ATF6, the activating tran-scription factor 6; PERK, the PKR like ER kinase; SREBP, sterol regulatory element binding protein, PON, paraoxonase.

Figure 3 Consequences of endoplasmic reticulum (ER) stress response. In the early phase, unfolded proteins cause dissociation of chaperones such as Bip/GRP78 from ER resident kinases-IRE1 and PERK and transcription factor-ATF6. Activated PERK phos-phorylates eIF2 resulting in translational attenuation. Activated IRE1 and ATF6 up-regulate genes encoding ER chaperone pro-teins such as GRP78/94 leading to increased protein-folding capacity. Overall, the unfolded protein response (UPR) goes down. In the late phase, IRE1 interacts with TRAF2 (tumor necrosis factor receptor associated factor 2) which activates caspases and JNK (cJUN NH2-terminal kinase) leads to apoptosis. ATF6 and PERK upregulate CHOP (C/EBP homologous protein) promoting cell death. SREBP upregulates lipid synthesis. Prolonged UPR leads to Ca²⁺ release from ER causing production of reactive oxygen intermediates which may lead to activation of NF-κB.

Figure 4 Hypothesis for the role of ethanol-induced HHcy in the pathogenesis of alcoholic liver disease.