Researchers Discover How a Molecule that Makes Fat and Helps Cancer Cells Grow is Produced

Thursday, September 27, 2018
Jason Locasale, PhD

Jason Locasale, PhD

Observational studies have long shown a connection between obesity and cancer in humans, but the biological processes linking them are not yet clearly understood by scientists.

A new metabolic pathway identified by scientists from Duke University in the journal Cell may explain an aspect of how excessive carbohydrate metabolism may help cancer cells to grow.

When a person consumes carbohydrates, the food is broken down into glucose, which can then be metabolized to create acetate. Acetate, commonly known as vinegar, is a molecule used to synthesize fat and also by cancer cells to proliferate.

Previously, it was known that bacteria could make acetate, but this study demonstrates that it is also made by human cells, said Jason Locasale, PhD, the paper’s senior author and an associate professor of pharmacology and cancer biology in the School of Medicine at Duke University. 

“Acetate has been in the scientific literature in many areas of biomedical research a lot in the past five years,” said Locasale.  “It didn’t seem likely that it was coming directly from any food source.  It just isn’t in very high quantities in the food we eat. We decided to revisit some of the glucose metabolism pathways to try to determine if they could be related.”

Ball and stick model of the acetate anionBall and stick model of the acetate anion

Locasale worked with lead author Xiaojing Liu, PhD, a former research associate at Duke who is now an assistant professor at North Carolina State University, to analyze glucose metabolism in biological samples from mice and human cells using mass spectrometry.  The researchers then tagged glucose and oxygen molecules and examined how they became metabolized into acetate over time.  The researchers partnered with David Kirsch, MD, PhD, the Barbara Levine University Professor in the Department of Radiation Oncology, to examine the fate of glucose and thus confirming that the pathway happens in live animals.

“Measuring acetate was a good start in this field but quantifying the contributions to endogenous acetate production via different mechanisms is very challenging,” said Liu.  “However, employing high resolution mass spectrometry and using multiple isotope tracers, especially the development of new technology using stable isotope labeled oxygen, we were able to quantify how much acetate is produced via different mechanisms. "
 
"The Locasale lab has discovered pathways for the production of acetate, including quantitation of a known chemical oxidation that produces acetate and a novel mechanism involving neomorphic enzymatic activity,” said Chi Van Dang, MD, PhD, scientific director of the Ludwig Institute for Cancer Research, who was not involved in the study. “These remarkable findings further add to our understanding of the complexity and flexibility of metabolic pathways, providing new insights into cancer cell survival under stressed conditions."

The discovery of the pathway may also have implications for the mechanisms that underlie some of the health benefits of the ketogenic diet, commonly known as “the Keto diet,” Locasale said.  The diet involves lowering carbohydrate intake and increasing fat intake in order to get your body to use fat for energy.  

“The acetate is coming from glucose and therefore used to make fat through this pathway so the production is linked to excessive carbohydrate metabolism,” said Locasale. “Therefore, one possible aspect of the health benefits of the Keto diet is through suppressing these acetate and fat producing pathways.  However, a lot more work in this area is needed to better understand this.”