New study reveals potential target for alcohol-associated liver disease
Discovery opens a path toward designing a new treatment for alcohol- associated liver disease

Date:
February 14, 2022
Source:
Cedars-Sinai Medical Center
Summary:
Researchers have uncovered a new pathway that helps explain how
consuming too much alcohol causes damage to the liver, specifically
mitochondrial dysfunction in alcohol-associated liver disease.



FULL STORY ========================================================================== Investigators at Cedars-Sinai have uncovered a new pathway that helps
explain how consuming too much alcohol causes damage to the liver,
specifically mitochondrial dysfunction in alcohol-associated liver
disease.


==========================================================================
The discovery, published in the peer-reviewed journal Nature
Communications, can also help lead to a new treatment approach for people suffering from the disease.

Cases of alcohol-associated liver disease continue to rise and is one of
the leading causes of alcohol-related deaths. The spectrum of the disease includes hepatitis, fibrosis to cirrhosis and liver cancer. Cirrhosis
alone causes 1.6 million deaths worldwide and over 50% of cases are due
to alcohol abuse.

Besides abstinence, there currently are no effective therapies for
treating people with the disease.

"Alcohol-associated liver disease is a major problem in the world," said
Shelly C. Lu, MD, director of the Karsh Division of Gastroenterology
and Hepatology in the Department of Medicine and senior author of
the study. "We've known for a long time that alcohol somehow damages mitochondria, but until now, it's not been clear as to what the mechanisms
are for this damage to occur." The liver is very rich in mitochondria,
known as the powerhouse of all cells, and plays a critical role in liver function. Alcohol, however, can alter the structure and function of the mitochondria, leading to liver injury.

To better understand the mechanisms for mitochondrial damage in alcohol- associated liver disease, Lu and her team looked at the role of an enzyme called MAT?1 that's responsible for providing the liver vital nutrients
for survival.



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

"Once we saw the depletion of MAT?1, we needed to figure out what was
making that happen," said Lucia Barbier-Torres, PhD, a postdoctoral
scientist in the Lu Laboratory and first author of the study.

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

"Once this interaction happens, MAT?1 cannot get into the mitochondria to provide the essential nutrient and instead gets degraded," Barbier-Torres
said.

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

"Our results support a novel and targetable mechanism to help treat
alcohol- associated liver disease," said Lu, who is also a professor of Medicine and the Women's Guild Chair in Gastroenterology.

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

Additional 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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Content may be edited for style and length.


========================================================================== Journal Reference:
1. Luci'a Barbier-Torres, Ben Murray, Jin Won Yang, Jiaohong Wang,
Michitaka
Matsuda, Aaron Robinson, Aleksandra Binek, Wei Fan, David
Ferna'ndez- Ramos, Fernando Lopitz-Otsoa, Maria Luque-Urbano, Oscar
Millet, Nirmala Mavila, Hui Peng, Komal Ramani, Roberta Gottlieb,
Zhaoli Sun, Suthat Liangpunsakul, Ekihiro Seki, Jennifer E. Van Eyk,
Jose M. Mato, Shelly C.

Lu. Depletion of mitochondrial methionine adenosyltransferase
a1 triggers mitochondrial dysfunction in alcohol-associated
liver disease. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022-28201-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214144025.htm

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