New Study Reveals How Trans Fats Drive Heart Disease Through Sphingolipid Metabolism

Salk Institute scientists have uncovered a key mechanism behind the harmful effects of trans fats, revealing how they contribute to atherosclerotic cardiovascular disease (ASCVD). Using mouse models, the researchers tracked how industrially produced trans-unsaturated fatty acids integrate into the body’s metabolic pathways, particularly through sphingolipid synthesis. Their findings, published in Cell Metabolism on November 14, 2024, could lead to new therapeutic targets for cardiovascular disease, non-alcoholic fatty liver disease, obesity, diabetes, peripheral neuropathy, and neurodegeneration.

Beyond Cholesterol: A New Player in Heart Disease

While excess cholesterol is a well-known cause of artery-clogging plaques, leading to strokes and heart attacks, the study sheds light on another class of lipids—sphingolipids—as a key driver of ASCVD. Scientists fed mice high-fat diets without additional cholesterol and found that trans fats were incorporated into sphingolipids, accelerating plaque formation.

This discovery shifts the focus from cholesterol alone to a broader understanding of cardiovascular risk factors. “We wanted to explore heart disease risk factors beyond cholesterol, and we identified an enzyme and pathway that could be targeted therapeutically,” says senior author Christian Metallo, professor at Salk.

How Trans Fats Fuel Plaque Formation

When dietary fats enter the body, they are processed into different lipids such as triglycerides, phospholipids, cholesterol, and sphingolipids. These lipids are then transported by lipoproteins like HDL, LDL, and VLDL.

Sphingolipids have been linked to ASCVD and other metabolic diseases, but their exact role remained unclear. Researchers hypothesized that trans fats, when processed by the enzyme serine palmitoyltransferase (SPT), might contribute to the secretion of VLDL—a major factor in arterial blockages.

To test this, they compared the effects of two fat types:

• Cis fats (found in natural foods like fish and walnuts) have a kink in their molecular structure, preventing tight packing and reducing the risk of arterial clogging.
• Trans fats (found in processed foods like margarine and fried items) have a straight-chain structure, allowing them to integrate into harmful lipid pathways.

Using metabolic tracing and physiological analyses, the team discovered that trans fats were preferentially metabolized by SPT, leading to increased lipoprotein secretion and plaque buildup.

Targeting SPT to Reduce Cardiovascular Risk

The researchers then tested whether inhibiting SPT could mitigate trans fat-induced ASCVD. Indeed, reducing SPT activity lowered plaque formation, suggesting that this enzyme could be a promising drug target for cardiovascular disease.

“As we learn more about these circulating molecules and their metabolism, we can make major advances in personalized medicine,” says Metallo. “For now, moderation in diet remains key.”

Global Implications and Future Research

Despite the World Health Organization’s push to eliminate trans fats, billions of people worldwide remain at risk. The researchers hope their findings will encourage stronger regulations and inspire new non-statin drugs to combat heart disease.

With a particular focus on an SPT subunit suspected of selectively expelling harmful lipids, future studies could pave the way for innovative treatments that go beyond traditional cholesterol-lowering strategies.

This research was supported by the National Institutes of Health, the Aileen S. Andrew Foundation, and the Mary K. Chapman Foundation.