Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also？ in vivo？？in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer. 1. Introduction The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells functioning in secretory protein synthesis and processing, lipid synthesis, calcium storage/release, and detoxification of drugs. The ER ensures correct protein folding and maturation. Unfolded proteins are retained in the ER and targeted for retrotranslocation to the cytoplasm for rapid degradation. Under normal physiological conditions, there is a balance between the unfolded proteins and the ER folding machinery. Disruption of the balance results in accumulation of unfolded proteins, a condition termed ER stress [1–5]. The ER stress triggers the unfolded protein response (UPR), which attenuates protein translation, increases protein folding capacity, and promotes degradation of unfolded proteins, thus restoring ER homeostasis. However, prolonged UPR leads to an attempt to delete the cell causing injuries. Molecular chaperones such as the glucose-regulated protein 78 (GRP78/BiP) interact with three ER membrane resident stress sensors: inositol-requiring enzyme-1 (IRE1α), transcription factor-6 (ATF6), and PKR-like eukaryotic initiation
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