Liver transplants associated with alcohol-related disease are increasing rapidly, and given the limited supply of organ donors, research is shifting towards addressing the pathology behind the disease.
At the forefront of this is Mengwei Zang, MD, PhD, an internationally recognized leader in chronic liver disease research at the University of Texas Health Science Center at San Antonio (UT Health San Antonio), who just won a groundbreaking five-year, $2.53 million grant from the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health.
Zhang, who is the university’s Sam Ann Barshop Institute on Longevity and Aging and the Joe R. and Teresa Lozano Long Professor in the Department of Molecular Medicine at the University of California, San Diego, will use the funding to develop innovative approaches to investigate the pathological mechanisms underlying alcohol-related liver disease.
This study represents a scientific frontier in alcoholic liver disease research and suggests that abnormal RNA splicing is a new causative factor, which may lead to new therapies that may prevent or reduce the need for transplants.
“Early transplantation for alcohol-related liver disease is now the fastest growing reason for liver transplantation,” Zhang said, “highlighting the real urgency of studying the mechanisms behind the development of alcohol-induced liver injury.”
Alcohol-related liver disease accounts for half of all liver disease deaths and is rising worldwide. The main characteristic of alcohol-related liver disease is an excess of fat in liver cells. Without proper intervention, it can progress to life-threatening conditions such as cirrhosis and liver cancer.
Although liver transplantation is only one of the available treatment options, concerns remain about a limited supply of donor livers and the risk of patients relapsing into alcohol use disorder after transplant.
As a result, many patients miss out on life-saving treatment, and some remain in poor health even after receiving a transplant.
To address this challenge, Zhang has led recent studies demonstrating that the adipogenic process is a key driver of the development and progression of alcohol-related liver disease. In particular, excessive ethanol intake induces the accumulation of lipids and fatty acids, disrupting hepatocyte homeostasis, which refers to the stability of a cell type that is critical for many liver functions.
Ethanol in this case refers to the diluted ethanol found in alcoholic beverages, not the fuel additives found in gas stations. Alcohol-induced lipid accumulation in liver cells leads to an amplified inflammatory response in the liver and liver cell death, posing a serious threat to health and ultimately leading to death.
RNA splicing is a factor
Ribonucleic acid (RNA) is a molecule found in most living organisms, and messenger RNA (mRNA) carries the code for DNA that essentially tells the body how to make a particular protein.
RNA splicing is a crucial cellular process by which precursor mRNA transcripts are converted into mature mRNA. It functions by removing introns (non-coding regions of RNA) and splicing exons (coding regions) back together, allowing multiple proteins to be produced from a single gene.
In a new study by Zhang’s team, the researchers propose abnormal RNA splicing as a contributing factor to the dysregulation of lipid metabolism in liver cells exposed to alcohol.
The team will use innovative RNA sequencing techniques to reveal the presence and abundance of RNA molecules and spliced isoforms, as well as lipodomic approaches that refer to the large-scale study of cellular lipid pathways and networks. They will combine this with the use of tissue-specific knockout mouse models to inactivate genes of interest in mice, to uncover the underlying causes of alcohol-related liver disease.
Lead researcher Zhang emphasized that the study focuses on addressing key health challenges associated with alcohol use disorder, such as understanding the complexities of metabolic and liver damage through interdisciplinary collaboration and impactful research.
She will collaborate with Xianlin Han, PhD, professor, and Masahiro Morita, PhD, assistant professor, in the Barshop Institute, and Zhijie “Jason” Liu, PhD, associate professor and CPRIT investigator in cancer research, in the Mays Cancer Center and Biotechnology Institute in the Department of Molecular Medicine at UT Health San Antonio.
Their efforts will focus on understanding whether and how specific RNA splicing abnormalities contribute to the development of alcohol-related liver injury, with the aim of developing targeted therapeutic strategies.
“Our research aims to find new targets and more reliable and effective treatments for alcohol-related liver damage, which often progresses to liver failure and other organ damage,” Zhang said. “Our goal is to combat the epidemic of alcohol-related liver disease and provide more treatment options to the patient population with alcohol use disorder.”
UT Health San Antonio is a key driver of San Antonio’s $44.1 billion healthcare and bioscience sector and is the largest academic research institution in South Texas with an annual research portfolio of $413 million.
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University of Texas Health Science Center at San Antonio
