In a new study, researchers have uncovered an unexpected connection between an imbalance of electrons in liver cells and many metabolic problems that increase the risk for conditions such as heart disease and fatty liver disease.
Their findings shine a light on the phenomenon known as reductive stress and how genetics and environmental factors such as diet influence this emerging disease risk factor.
The research was conducted by a team at Massachusetts General Hospital.
Reductive stress occurs when cells build up an overabundance of electrons, which play an essential role in producing energy.
According to the team, the food people eat tends to be very rich in electrons.
But if there’s an imbalance between the supply and demand for those electrons—specifically, an excess supply—people can get reductive stress.
Eating a high-fat diet and consuming alcohol can cause reductive stress in liver cells.
While reductive stress has been linked to certain rare genetic disorders known as mitochondrial diseases, its role in more common conditions has not been well studied.
In the study, the team found a genetically engineered enzyme called LbNOX prevented mice that drank alcohol from developing reductive stress.
The finding showed that doctors can use this genetic tool to control reductive stress in the liver
The team identified a metabolite in the blood called alpha-hydroxybutyrate that rose when electrons built up in liver cells.
Alpha-hydroxybutyrate levels are linked to insulin resistance, a risk factor for type 2 diabetes, and obesity.
Previous genetic analysis linked alpha-hydroxybutyrate levels in humans to a variant in a gene called GCKR, which occurs in about 50 percent of people and seems to affect risk for many diseases and unhealthy traits, such as fatty liver disease and elevated levels of blood fats called triglycerides.
They showed that the GCKR mutation in mouse liver cells was linked to high levels of alpha-hydroxybutyrate, linking it to reductive stress.
Importantly, this study found that treating reductive stress with LbNOX lowered levels of triglycerides, which increase the risk for heart disease, and improved metabolic factors, including insulin resistance.
The team believes alpha-hydroxybutyrate could be used as a biomarker to test for reductive stress and that LbNOX may one day serve as a treatment for diseases caused by metabolic dysfunction.
One author of the study is Vamsi Mootha, MD from Mass General’s Department of Molecular Biology.
The study is published in the journal Nature.
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