Researchers at Massachusetts General Hospital have uncovered a connection between electron imbalance in liver cells and metabolic conditions. Their findings, published yesterday in Nature, 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.
Reductive stress occurs when cells build up an overabundance of electrons, which play an essential role in producing energy. “The food we eat tends to be very rich in electrons,” says senior author Vamsi Mootha. “But if there’s an imbalance between the supply and demand for those electrons—specifically, an excess supply—you 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.
“Alcohol generates a ton of electrons, and that causes a lot of reductive stress,” says first author Russel Goodman.
Yet when the team administered a genetically engineered enzyme called LbNOX to the livers of lab mice that had been given alcohol, the mice were prevented from developing reductive stress. “The study showed that we can use this genetic tool to control reductive stress in the liver,” Goodman says. “We can give it and take it away.”
The team identified a metabolite in the blood called alpha-hydroxybutyrate that rose when electrons built up in liver cells. This intrigued the investigators, since alpha-hydroxybutyrate levels are associated with insulin resistance. Previous genetic analysis linked alpha-hydroxybutyrate levels in humans to a variant in a gene called GCKR, which occurs in about 50% of people and seems to affect risk for many diseases and unhealthy traits, such as fatty liver disease and elevated levels of triglycerides. They showed that the GCKR mutation in mouse liver cells was associated with high levels of alpha-hydroxybutyrate, linking it to reductive stress.
Importantly, this study found that treating reductive stress with LbNOX lowered levels of triglycerides and improved metabolic factors, including insulin resistance.
Mootha 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. “LbNOX is empowering a new class of studies we call ‘causal metabolism,’” Mootha says. “They are allowing us, for the first time, to manipulate metabolism in living organisms and see what the consequences are.”