COVID-19 Virus Uses Body’s Fat-Processing System to Fuel Replication

Researchers at the Department of Energy’s Pacific Northwest National Laboratory (PNNL) and Oregon Health & Science University (OHSU) have found that the virus that causes COVID-19 undertakes a massive takeover of the body’s fat-processing system, creating cellular storehouses of fat that empower the virus to hijack the body’s molecular machinery and cause disease. The study, published recently in Nature Communications, also found that use of weight-loss drugs and other fat-targeting compounds stopped replication of the virus in cell culture within 48 hours.

Though the authors caution that much more research is needed, they believe the findings could be a significant step toward understanding the virus. “This is exciting work, but it’s the start of a very long journey,” says Fikadu Tafesse, the corresponding author of the study and assistant professor of molecular microbiology and immunology at OHSU. “We have an interesting observation, but we have a lot more to learn about the mechanisms of this disease.”

The team embarked on the study based on observations that people with a high body-mass index and conditions like cardiovascular disease and diabetes are more sensitive to the disease.

Using two different human cell lines, the team studied the effect of SARS-CoV-2 on more than 400 lipids. Scientists found a massive shift in lipid levels, with some fats increasing as much as 64-fold. In one cell line, nearly 80% of fats were altered by the virus; in the other, levels of slightly more than half were changed.

The lipids affected most were triglycerides, those little packets of fat that most patients try to keep to a minimum. Triglycerides are crucial for our health, allowing us to store energy and to maintain healthy membranes in our cells, but also, it turns out, vital to the COVID virus.

“Lipids are an important part of every cell. They literally hold us together by keeping our cells intact, and they’re a major source of energy storage for our bodies,” says Jennifer Kyle, a biomedical scientist at PNNL who specializes in the measurement of lipids. “They are an attractive target for a virus.”

When we need energy, cells break up the triglycerides into useful raw material—three fatty acids that each triglyceride molecule contains. The team found that SARS-CoV2 doesn’t simply boost the number of triglycerides in our cells. The virus also changes much of our fat-processing system, changing the body’s ability to use fat as fuel. The team also evaluated the effects of 24 of the virus’s 29 proteins on lipid levels.

The team identified a handful of viral proteins whose effect on triglyceride levels was particularly strong. Based on the findings, the team searched databases and identified several compounds that might have potential to disrupt the body’s fat-processing system. Several proved effective at stopping the virus from replicating in the laboratory. An approved weight-loss medication, Orlistat, a lipase inhibitor, stopped viral replication. An experimental compound known as GSK2194069 also stopped the virus. These and other compounds worked against all the SARS-CoV2 variants tested: alpha, beta, gamma and delta.

“As the virus replicates, it needs a continuous supply of energy,” said Tafesse, whose team has also seen lipid changes as a result of Zika virus and HIV. “More triglycerides could provide that energy in the form of fatty acids. But we don’t know exactly how the virus uses these lipids to its advantage.”