Liver transplants associated with alcohol-related disease are growing at a rapid pace, shifting research to address pathologies behind the ailments in light of a limited supply of organ donors.
At the forefront 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 was just awarded a groundbreaking five-year, $2.53 million grant from the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health.
Zang, professor at the university’s Sam and Ann Barshop Institute for Longevity and Aging Studies and the Department of Molecular Medicine at the Joe R. and Teresa Lozano Long School of Medicine, will use the funding to develop innovative approaches to investigate the pathological mechanisms underlying alcohol-associated liver disease.
The research represents a scientific frontier in the study of alcoholic liver disease, proposing abnormalities in RNA splicing as a new causative factor. It could result in new treatments to forestall or reduce the need for transplants.
“Early transplantation for alcohol-associated liver disease is currently the fastest-growing reason for liver transplants,” Zang said, “highlighting the real urgent need to study the mechanisms driving the pathogenesis of alcohol-induced liver damage.”
Alcohol-associated liver disease accounts for half of liver disease-related deaths, and its rates are rising worldwide. The main characteristic of alcohol-associated liver disease is excess fat in liver cells. Without proper intervention, it may progress to life-threatening conditions such as cirrhosis and liver carcinoma.
Although liver transplantation is only one treatment option available, concerns persist about the short supply of donor livers and the risk of patients relapsing into alcohol use disorder post-transplantation.
As a result, many patients lack access to life-saving treatments, while others continue to have poor health even after receiving a transplant.
To address this challenge, Zang has led recent research showing that the lipogenic process is a critical factor in the initiation and progression of alcohol-associated liver disease. Particularly, excessive ethanol consumption induces lipid or fatty acid accumulation and disrupts hepatocyte homeostasis, which refers to the stability of a cell type important to many liver functions.
Ethanol, in this case, doesn’t refer to the fuel additive at the gas pump, but rather a diluted form present in alcoholic drinks. Alcohol-induced lipid accumulation in hepatocytes triggers an amplified inflammatory response and hepatocyte death within the liver, posing a significant threat to health and eventually culminating in death.
RNA splicing as a factor
Ribonucleic acid, or RNA, is a molecule present in the majority of living organisms, and messenger RNA, or mRNA, carries codes from DNA that essentially tell the body how to make specific proteins.
RNA splicing is a critical cellular process in which a precursor mRNA transcript is transformed into mature mRNA. It works by removing introns, or non-coding regions of RNA, and splicing back together exons, or coding regions, which enables the production of diverse proteins from a single gene.
For the new study by Zang’s team, investigators have proposed RNA splicing abnormality as a factor that contributes to dysregulated lipid metabolism in hepatocytes exposed to alcohol.
The team will use innovative RNA sequencing, to reveal the presence and quantity of RNA molecules or spliced isoform, and lipodomics approaches, referring to the large-scale study of pathways and networks of cellular lipids. They will combine that with the use of tissue-specific knockout mouse models, in which genes of interest are inactivated in mice, to uncover the root causes of alcohol-associated liver disease.
Zang, as principal investigator, emphasizes that the study is focused on addressing major health challenges associated with alcohol use disorder, such as understanding the complexities of metabolic disorders and liver damage through interdisciplinary collaboration and impactful research.
She will collaborate with Xianlin Han, PhD, professor, and Masahiro Morita, PhD, assistant professor, both with the Barshop Institute; and Zhijie “Jason” Liu, PhD, associate professor and CPRIT Scholar in Cancer Research with Mays Cancer Center and the Institute of Biotechnology of the Department of Molecular Medicine at UT Health San Antonio.
Their efforts will focus on understanding if and how specific RNA splicing abnormalities contribute to the pathogenesis of alcohol-related liver damage, in an effort to develop targeted treatment strategies.
“Our investigation aims to discover novel targets and more reliable, effective treatments for alcohol-related liver injury that often progresses to liver failure and other organ damage,” Zang said. “Our objective is to combat the epidemic of alcohol-associated liver disease and to provide more treatment options for the alcohol use disorder patient population.”
UT Health San Antonio is a primary driver of San Antonio’s $44.1 billion health care and biosciences sector, and is the largest academic research institution in South Texas with an annual research portfolio of $413 million.
