Discovery paves way for design of new treatment for alcohol-related liver disease

Cedars-Sinai researchers have discovered a new pathway that helps explain how excessive alcohol consumption causes liver damage, specifically mitochondrial dysfunction in alcohol-associated liver disease.

The discovery, published in the peer-reviewed journal Nature Communicationmay also contribute to a new therapeutic approach for people with the disease.

Cases of alcohol-related liver disease continue to rise and are one of the leading causes of alcohol-related death. The spectrum of disease includes hepatitis, fibrosis to cirrhosis, and liver cancer. Cirrhosis alone causes 1.6 million deaths worldwide and more than 50% of cases are due to alcohol abuse. Other than abstinence, there is currently no effective therapy to treat people with the disease.

“Alcohol-associated liver disease is a major problem worldwide,” said Shelly C. Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology in the Department of Medicine and lead study author. . “We’ve known for a long time that alcohol somehow damages mitochondria, but until now the mechanisms by which this damage occurs has been unclear.”

The liver is very rich in mitochondria, known as the powerhouse of all cells, and plays a vital role in liver function. Alcohol, however, can alter the structure and function of mitochondria, leading to liver damage.

To better understand the mechanisms of mitochondrial damage in alcohol-related liver disease, Lu and his team examined the role of an enzyme called MAT?1 that is responsible for supplying the liver with vital nutrients for survival.

Using liver tissue from patients with alcohol-associated liver disease and preclinical models, the team found that levels of this enzyme were selectively reduced in mitochondria.

“Once we saw MAT?1 depletion, we needed to figure out what was causing it to happen,” said Lucia Barbier-Torres, PhD, postdoctoral scientist at the Lu lab and first author of the study.

The team found that alcohol activates protein casein kinase 2 (CK2), which triggers a process called phosphorylation of MAT?1 at a specific amino acid residue. In their experiments, the team found that this process facilitates an interaction between MAT?1 with another protein called PIN1 and prevents MAT?1 from being transported into the mitochondria.

“Once this interaction occurs, MAT?1 cannot enter the mitochondria to deliver the essential nutrient and instead degrades,” Barbier-Torres said.

With this information, the team decided to block this interaction by turning off MAT?1, thereby preventing phosphorylation from occurring. This prevented the interaction of the two proteins, preserving the location and function of mitochondrial MAT?1 in the mitochondria and thus protecting the mitochondria from being damaged by alcohol consumption. They observed the same protection when they reduced CK2 expression to lower MATß1 phosphorylation.

“Our findings support a new, targetable mechanism to help treat alcohol-associated liver disease,” said Lu, who is also a professor of medicine and the Women’s Guild Chair of Gastroenterology.

The next steps in this line of research for Lu and his team include the development of small molecule therapeutics that can interfere with the interaction between MAT?1 and PIN1, which should protect mitochondria from alcohol-induced damage.

Other Cedars-Sinai co-authors include Ben Murray, Jin Won Yang, Jiaohong Wang, Michitaka Matsuda, Wei Fan, Nirmala Mavila, Hui Peng, Komal Ramani, Ekihiro Seki, and Jennifer Van Eyk.

Funding: The research was supported by the National Institutes of Health under award numbers R01AA026759 and R01DK123763.

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