Blocking the EFHD1 protein protects against progression to MASH

Researchers are beginning to understand why a person with fatty liver may not progress to metabolic dysfunction-associated steatohepatitis (MASH), a disease that causes the liver to swell and can lead to cirrhosis, liver cancer and liver failure. MASH is linked to Type 2 diabetes and other metabolic conditions such as obesity and affects about 7% of the global population.

University of Utah Health researchers have discovered that the protein EFHD1, which has been shown to be involved in cancer growth, may also play a role in the development of MASH, according to new research published in the Journal of Clinical Investigation. Researchers have found that blocking EFHD1 can protect against liver injury in both human cells and mouse models.

“This research may help people by identifying new biological pathways that can be targeted with drugs to help stave off liver disease by limiting how fat buildup damages the liver,” David Eberhardt, Ph.D., postdoctoral associate in internal medicine at University of Utah Health and first author on the study, said in a news release.

The study was led by Eberhardt and Dipayan Chaudhuri, M.D., Ph.D., a cardiologist and associate professor of internal medicine at University of Utah Health. Their research found that EFHD1 could lead to a separate pathway that determines whether a fatty liver becomes damaged. “The amount of lipid itself is not the only factor causing injury; that threshold varies a lot," Chaudhuri said.

Previously, Chaudhuri and his colleagues had linked EFHD1 to heart attack-like injury in mice. They have also found that EFHD1 was associated with elevated liver enzymes. With the current research, they wanted to determine how a fatty liver actually becomes damaged and whether EFHD1 plays a role. EFHD1 acts as a calcium sensor within the mitochondria, which generates the energy needed for the cells’ biochemical reactions. Calcium is a key element in this process.

Chaudhuri and his colleagues examined mice that had been genetically engineered without the EFHD1 protein. In these mice, liver mitochondria appeared stretched into long, spaghetti-like strands rather than their normal compact bean shape. Using biochemical and imaging tests, they found that EFHD1 tethers mitochondria to a nearby organelle called the endoplasmic reticulum. The mitochondria’s odd shape means they don’t divide as often.

When mice are fed a fatty, sugary diet that induces liver injury, excess lipids drive up EFHD1 levels, which makes mitochondria divide so much that they start leaking their contents into the rest of the cell. Those contents include double-stranded RNA, which can also appear in the main body of the cell if it’s been infected by certain viruses, such as hepatitis C.

When the cell detects mitochondrial RNA in the cytoplasm, it activates an antiviral defense pathway, and the cell’s antiviral response causes additional injury to the liver. “It's almost like obesity is making the liver think it’s under viral attack,” Chaudhuri said.

Researchers then blocked or reduced the levels of EFHD1, and they found that measures of inflammation and liver scarring dropped by roughly 30 to 60% in mice, as well as in human liver cells.

The research team is currently working to develop therapies to decrease EFHD1 levels, building on work covered by a patent filed by the university.