Byoung-Joon (B.J.) Song, Ph.D.

The overall goals of my lab projects are to perform basic research to study the molecular mechanisms of cell/organ injury and to conduct translational research with dietary antioxidants to prevent tissue damage caused by ethanol (binge alcohol) alone or in the presence of other risk factors in experimental models. Alcohol and many other potentially toxic compounds [e.g., acetaminophen, carbon tetrachloride, thioacetamide, Western-style high-fat diet (HFD), fructose, lipopolysaccharide, nicotine, cisplatin, etc.] are known to stimulate cell/organ injury through increased oxidative and nitrative stress. Elevated levels of oxidative stress are also observed in many pathophysiological conditions (e.g., metabolic syndrome, obesity, diabetes, viral infection, ischemia-reperfusion injury, aging-related neurodegeneration, etc.). However, the mechanisms by which elevated oxidative stress stimulates cell/tissue damage are still poorly understood. Thus, we hypothesized that increased oxidative stress causes different types of post-translational modifications (PTMs) of cellular proteins with suppression of their functions/activities, leading to mitochondrial dysfunction, ER stress, impaired autophagy, and activation of the pro-apoptosis signaling pathway, all of which can contribute to multiple organ damage through the gut-liver-brain axis.

To study the causal or contributing roles of oxidative PTMs in mitochondrial dysfunction, ER stress, and cell/tissue injury, we have developed specific methods to determine various PTMs of proteins in different sub-organelles of cultured cells and animal tissues (including a few genetically altered mice) after treatment with different doses of ethanol alone or in combination with another risk factor listed above. By carefully studying the time-dependent changes in oxidative PTMs and cell/tissue injury, we demonstrated the causal or contributing roles of various PTMs, such as oxidation, nitration, phosphorylation, acetylation, and adducts of mitochondrial and ER proteins after exposure to binge alcohol or a Western-style HFD, in promoting mitochondrial dysfunction, ER stress, and apoptosis, contributing to alcohol-associated and metabolic dysfunction-associated steatotic liver disease (AFLD and MASLD, respectively) or acute liver injury, usually observed at later times. We have specifically studied the opposing roles of ethanol-inducible cytochrome P450-2E1 (CYP2E1) and mitochondrial aldehyde dehydrogenase-2 (ALDH2) in oxidative modifications of tight and adherens junction proteins in intestinal epithelial and brain endothelial cells, contributing to binge alcohol-mediated gut leakiness with elevated levels of serum endotoxin, pro-inflammatory cytokines, and liver or brain injury. Our results showed that Cyp2e1-knockout (KO) mice were quite resistant to binge alcohol- or Western-style HFD-induced oxidative PTMs, gut leakiness, and tissue damage, suggesting the critical role of CYP2E1 in promoting intestinal barrier dysfunction, endotoxemia, and liver or brain injury through the gut-liver-brain axis. In contrast, Aldh2-KO mice were very sensitive to binge alcohol-mediated oxidative PTMs and gut, liver, and injury. Based on our recent results, we also studied the opposing roles of CYP2E1 and ALDH2 in blood-brain barrier disruption and brain damage by following the well-established model of a 4-day binge alcohol exposure, other neurotoxic agents, or aging.

Based on our mechanistic study results, we have also conducted translational research by evaluating the beneficial effects of various dietary antioxidants, including pomegranates, ellagic acid, n-3 fatty acids, and walnuts against leaky gut, AFLD, and MASLD. Our results revealed that physiologically relevant levels of many dietary supplements can prevent alcohol- or HFD-mediated leaky gut, endotoxemia, and inflammatory tissue injury. We believe that our basic mechanistic studies can ultimately lead to future preclinical research for the development of an effective agent against oxidative organ damage caused by excessive alcohol, nonalcohol substances, and aging or other pathological conditions.

Dr. Byoung-Joon (B.J.) Song received his B.S. and M.S. degrees from Seoul National University, Seoul, Korea. He then received his Ph.D. degree from the Department of Pharmacology, University of Minnesota Medical School. He completed his post-doctoral training under Dr. Frank F. Gonzalez and the late Dr. Harry V. Gelboin at the National Cancer Institute, NIH from 1983-1986. He joined the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a Senior Staff Fellow in 1986 and has then served as a Senior Investigator and Chief of Section of Molecular Pharmacology and Toxicology at the NIAAA since 1993.