At UT Southwestern Medical Center, researchers made a surprising discovery about the heart's relationship with fat—one that upends decades of conventional wisdom about what the organ needs to thrive. When heart muscle cells burn fat without the proper metabolic brakes, they don't just run hot; they systematically destroy the very structures that power every heartbeat, according to a new study published in the Journal of Clinical Investigation.
The culprit is a cascade triggered by unrestrained fat oxidation, the process cells use to break down fats for energy. Normally, heart cells regulate this process through two enzymes called acetyl-CoA carboxylase 1 and 2, which control how many fatty acids enter the mitochondria—the cell's energy-generating powerhouses. To understand what happens when this control fails, researchers genetically removed these enzymes from mouse heart muscle cells. The result was swift and devastating: the mice developed enlarged hearts and impaired blood-pumping function.
The mechanism they uncovered reveals a hidden cost of unfettered fat burning. Unrestrained fatty acid oxidation depletes linoleic acid, a dietary fatty acid the heart needs to maintain cardiolipin, a critical structural lipid essential for mitochondrial function. As cardiolipin levels dropped, the mitochondria's energy-producing machinery faltered, and the mice developed dilated cardiomyopathy—a form of heart failure characterized by an enlarged, weakened heart that struggles to pump blood effectively.
"This study challenges a long-held assumption that maximizing fat burning is beneficial for the heart," said Jay Horton, M.D., Director of the Center for Human Nutrition and senior author of the research. "It demonstrates that unrestrained fatty acid oxidation paradoxically destroys the heart's own mitochondrial architecture through depletion of cardiolipin, an essential structural lipid." The findings help explain a longstanding puzzle in cardiology: as heart failure develops, the heart often shifts away from fat metabolism and relies more heavily on glucose instead—a pattern researchers had debated for years.
The team tested a therapeutic approach to prevent this damage. Using drugs that inhibit CPT1, a protein that transports fatty acids into mitochondria, they were able to prevent heart failure when the medication was given early, before cardiac dysfunction took hold. However, the same approach failed once cardiomyopathy was already established, suggesting that timing is critical for any future therapy targeting heart metabolism.
"Timing matters for FAO-targeted therapy for heart failure," said Chai-wan Kim, Ph.D., Assistant Professor in the Center for Human Nutrition and first author of the study. This finding points to the importance of early detection and intervention—identifying which patients face metabolic imbalance in the heart before irreversible damage occurs.
The broader implication of this work is that the heart doesn't simply need more or less fat burning; it needs metabolic flexibility. "The goal should not simply be to increase or decrease FAO," Dr. Horton emphasized. "Instead, the heart needs metabolic flexibility that keeps FAO within a healthy range. This balance is important for both energy production and mitochondrial health." These preclinical results open new avenues for understanding heart failure risk and suggest that cardiolipin and related mitochondrial lipids might serve as early warning markers—or even targets for new treatments designed to protect the heart before serious dysfunction develops.