Research Medicine, Biochemical & Molecular Biology
Keck School of Medicine of USC
- Organelle Stress & Liver Diseases;
- Hepatotoxicity of anti-HIV/HCV Drugs and Alcohol;
- Alcoholic Hyperhomocysteinemia;
- Tackling Alcohol Intoxication with Nanotechnology
Research OverviewHeavy or long-term alcohol consumption is a major cause of acute and chronic liver disease worldwide and increasingly contributes to human mortality. Alcohol induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis has recently been established as a significant mechanism contributing to liver diseases. The ER stress occurs not only in cultured hepatocytes but also in vivo in the livers of several species including 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) New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases. Int. J. of Hepatology, vol. 2014; 513787; PMID: 2486870
(2) Critical Role of GRP78 in Pulmonary Microvascular Remodeling
Gene. 2014; 545(1):156-62; PMID: 24768185
(3) Expression of GRP78 in hepatopulmonary syndrome.
Gene. 2014; 537:115-119; PMID: 24334118
(4) Altered Methylation of ERAD in Alcohol-induced Liver Tumors.
Frontiers in Genetics 2013; 4: 224; PMCID: PMC3813967
(5) Enzyme Nanocomplexes as Antidotes for Alcohol Intoxication
Nature Nanotech. 2013; 8:187
(6) ER stress, Cyclin D, ERα variants, and Liver Tumorigenesis
J Gastro. Hepatol. 2013; 28(3):576
(7) Tregs, MMP9/13, TGF-β and acute liver injury. J Mol Cell Biol. 2013; 5(6):369-79.