TC (Training Core)
Speaker: Xiao-Ming Yin, M.D., Ph.D.
Director of Clinical Laboratories, Indiana University Health Pathology Laboratory and Vice Chairman for Clinical Pathology Department of Pathology and Laboratory Medicine Indiana University, School of Medicine
Seminar Title: "Autophagy in Fatty Liver Disease”
Hosted by Dr. Ekihiro Seki, UCSD SRC Project Leader
December 19, 2014 | Meeting Summary By: Mei-Fei Yueh, Ph.D. Web content: Michelle Feiock, Program Manager and Bethany Behnke, Assistant
In the Distinguished Seminar Series, we were honored to have as our speaker Xiao-Ming Yin, M.D., Ph.D., the Louis Y. Mazzini Professor of Pathology and Director of Clinical Laboratories, Indiana University Health Pathology Laboratory. One of his laboratory research focuses is the regulation of macroautophagy in liver disease. Macroautophagy (“autophagy”) - an intracellular degradation system encoded by a number of ATG genes – is responsible for the degradation of macromolecules and subcellular organelles and is most closely associated with human disease (compared to microautophagy and chaperone-mediated autophagy). As autophagy is commonly activated in response to a variety of stress conditions (such as starvation), Dr. Yin’s laboratory has been exploring how autophagy regulates cellular homeostasis in hepatocytes in response to ethanol- or high fat diet (HFD)-induced liver pathogenesis.
Previous studies in Dr. Yin’s laboratory have demonstrated that ethanol could induce the autophagy process in primary hepatocytes dependent on ethanol metabolism (by CYP2E1), ROS generation, and mTOR inhibition. It is also known that autophagy has the ability to remove and decrease intracellular lipid droplets. Fatty liver disease – including alcohol and non-alcoholic fatty liver conditions – is the early response of liver pathogenesis, can progress and manifest to steatohepatitis, fibrosis, and cirrhosis, and has significantly increased in the era of obesity epidemic. By promoting or inhibiting autophagy through pharmacological modulators of autophagy, Dr. Yin’s laboratory conducted a series of experiments and examined the impact of autophagy on fatty liver due to ethanol feeding or high fat diet.
They found that both carbamazepine and rapamycin – acting as autophagy activators by suppressing mTOR activity - promote autophagy in hepatocytes. When mice were treated with these autophagy activators, they reduce steatosis, liver injury, ALT elevation, and lipid droplets following acute or chronic ethanol feeding in mice. In contrast, chloroquine, which blocks autophagy, exacerbates stenosis, the accumulation of lipid droplets, and liver injury in these animals. In combination with previous results, Dr. Yin concluded that although ethanol-induced autophagy did not affect protein degradation, it is selective for damaged mitochondria and accumulated droplets and plays a protective role by limiting ethanol-induced liver toxicity.
To explore fatty liver disease induced by a high fat diet (HFD), Dr. Yin’s team found that carbamazepine and rapamycin significantly reduce stenosis, hepatic and serum triglycerides, and insulin resistance when mice were fed a HFD for 12 weeks, indicating that autophagy inducing agents are benefiting fatty liver by increasing autophagy. These studies point out the potential treatment of fatty liver due to ethanol or HFD by stimulating autophagic flow using pharmacological modulators.
The transcription factor EB (TFEB) has been identified as one of the transcription factors that regulate autophagy gene expression. Following a HFD feeding in mice, Dr. Yin’s laboratory discovered the following signaling events: mTOR can be activated through a HFD, which in turn suppresses TFEB, subsequently affects lysosome function, and returns back to regulate mTOR activation, forming an mTOR-TFEB feedback loop and contributing to autophagy degradation. Another phenomenon they discovered is that mTOR modulation is rather dynamic and exhibits an oscillation pattern, which is conversely correlated with TFEB and lysosome activities at the different time points throughout the course of HFD treatment. These studies imply that suppression of mTOR and promotion of TFEB along with autophagy enhancement may be an effective therapeutic approach for treating fatty liver disease.
Xiao-Ming Yin, MD, PhD
IU Health Pathology Laboratory
350 West 11th Street, Room 6016A
Indianapolis, IN 46202-4108
Project 6 - Schroeder
Project 5 - Chang
"Probes Sensors and Small Molecule Toxicants"
RTC/CEC - Pezzoli
"Sharing SRC Science Through Community Engagement and Research Translation"
RSC (Genetics and Metabolomics Core) - Mellon/Jain
Project 2 - Evans
"Elucidating the Role of Nuclear Hormone Receptor and Epigenetic Signaling in Toxicant Associated SteatoHepatitis"
TC - McNulty/Schoeller
"Deletion of the Circadian Gene, Bmal1, Affects Cytochrome p450 Gene Expression in the Liver"
"Elucidating the Structure and Mechanism of Bacterial and Toxicant-Induced Inflammasome Activation"
Project 4 - Brenner
"Epigenetics of CCl4 Induced Liver Fibrosis"
Project 1 - Karin
“Immune control of liver tumorigenesis – basic concepts and implications for treatment"
UCSD Superfund Research Center
University of California, San Diego
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722