A protein inside the “energy factories” of liver cells appears to trigger the damage seen in some patients with fatty liver disease, researchers have discovered.
Obesity-related liver disease affects hundreds of millions of people worldwide, but only a fraction of those livers develop scarring, become inflamed, and eventually fail, the researchers noted in a report published on Tuesday in the Journal of Clinical Investigation.
EFHD1, a calcium-binding protein in the membrane of the mitochondria, drives that process, they found. Blocking it protects against liver injury in human cells and in mice consuming a high-fat diet.
Using biochemical and imaging tests, the team found that EFHD1 tethers mitochondria to a nearby organelle called the endoplasmic reticulum and helps trigger mitochondrial division.
When mice are fed a fatty, sugary diet, excess lipids drive up EFHD1 levels, which makes the 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 presence of certain viruses, like hepatitis C. Upon detecting the double-stranded RNA, the cell activates an antiviral defense pathway.
That response, meant to prevent viral replication in infected cells, instead shuts down healthy liver cells, worsening injury, according to the researchers.
When the researchers blocked or reduced the levels of EFHD1, measures of inflammation and liver scarring dropped by roughly 30% to 60% in mice with liver injuries resulting from diet or drug treatments and in miniature models of human livers in test tubes.
The researchers also found that mice engineered to lack EFHD1 have normal activity levels, weight gain, and other measures of metabolism, which suggests that treatments that block EFHD1 may have few side effects. They said they are currently working to develop such a drug.
“This research may help people by identifying new biological pathways which can be targeted with drugs to help stave off liver disease by limiting how fat buildup damages the liver,” study leader David Eberhardt of University of Utah Health said in a statement.
