Reducing liver fibrosis

New study identifies targets to lessen the effects of alcoholic liver disease
November 30, 2017

Nearly half of the estimated 78,529 liver disease deaths among Americans 12 and older were related to alcoholic liver disease in 2015, according to the National Institute on Alcohol Abuse and Alcoholism. This is because over time, alcohol consumption causes abnormal fat accumulation in liver cells, called steatosis, as well as the formation of excess fibrous connective tissue in the liver, a process called fibrosis. This, in turn, can lead to hepatitis, cirrhosis (scarring of the liver) and liver cancer.

A new study in The American Journal of Pathology offers insights into the cellular aging that may trigger liver fibrosis, as well as possible means to inhibit these changes, which may lead to new therapeutic approaches for patients with alcoholic liver disease.

“We believe that senescent cells contribute to age-related tissue degeneration during chronic liver injuries,” said Fanyin Meng, PhD, associate professor of internal medicine at the Texas A&M College of Medicine, researcher with Baylor Scott & White Digestive Disease Research Center (DDRC), investigator for Central Texas Veterans Health Care System (CTVHCS), and co-corresponding author of the study. “Cellular senescence refers to the irreversible stopping of the normal cell cycle combined with the secretion of pro-inflammatory compounds called cytokines. Our study demonstrates that these drivers of aging are critical mediators of alcoholic liver diseases.”

Investigators studied liver tissue from patients with fatty liver disease, or steatohepatitis, who were heavy alcohol drinkers. They also examined ethanol-fed animal models to identify biochemical markers of cellular senescence. Their findings indicate that increasing the amount of a tiny bit of genetic material called microRNA-34a during alcohol consumption contributes to the development of liver fibrosis during alcoholic liver injury. At the same time, the opposite is also true: decreasing the expression of this microRNA in the liver reduces liver injury and liver fibrosis in alcoholic liver disease.

“Targeting the drivers of aging and senescent cells may be a novel therapeutic strategy to reduce hepatic steatosis and liver fibrosis in alcoholic liver disease patients,” said co-corresponding author Gianfranco Alpini, PhD, Distinguished Professor of medical physiology at Texas A&M College of Medicine, director of DDRC and Research Career Scientist with CTVHCS.

According to the study’s findings, the up-regulation of microRNA-34a due to alcohol has different effects on the two types of cells found in the liver. In hepatocytes, the primary liver cells that make up 70 to 85 percent of the liver’s mass and carry out the basic functions of the liver, senescence is increased. On the other hand, senescence is decreased in activated hepatic stellate cells, the supportive cells which, when triggered by alcohol or other liver insults, begin to produce excessive fibrotic material.

“Understanding the mechanisms underlying hepatic stellate cell activation and regression has become an increased area of interest,” Meng said, “and our findings help to advance understanding of the complex nature of this phenomenon.”

More broadly, this pathway that regulates hepatic stellate cell activation and regression could potentially be applied to other aging-associated fibrotic liver diseases.

“It is imperative to identify regulatory targets for potential treatment of alcoholic liver diseases, especially for populations that are greatly impacted by this disease,” added Heather Francis, PhD, and Shannon Glaser, PhD, associate professors of medical physiology at Texas A&M, DDRC, CTVHCS, and co-authors of the article. “Our study opens the window for the possibility of linking age-related genes as therapeutics for the future.


The article is “Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury,” by Ying Wan, Kelly McDaniel, Nan Wu, Sugeily Ramos-Lorenzo, Trenton Glaser, Julie Venter, Heather Francis, Lindsey Kennedy, Keisaku Sato, Tianhao Zhou, Konstantina Kyritsi, Qiaobing Huang, Tami Annable, Chaodong Wu, Shannon Glaser, Gianfranco Alpini, and Fanyin Meng ( It will appear in The American Journal of Pathology, volume 187, issue 12 (December 2017) published by Elsevier.

This research was partially funded by a VA Merit Award (1I01BX001724) to Dr. Meng, the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Baylor Scott & White, a VA Research Career Scientist Award and a VA Merit award to Dr. Alpini (5I01BX000574), a VA Merit Award (5I01BX002192) to Dr. Glaser, and the NIH grants DK058411, DK076898, DK107310, and DK062975 to Drs. Alpini, Meng and Glaser. Portions of this work were supported by a VA Merit Award (1I01BX003031) from the United States Department of Veteran’s Affairs, Biomedical Laboratory Research and Development Service and an RO1 from NIH NIDDK (DK108959) (HF).

— Christina Sumners

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