Researchers at the Salk Institute have observed how trans fats impact the body using mouse models, uncovering the molecular mechanisms that link these fats to atherosclerotic cardiovascular disease (ASCVD). Their findings highlight the significant risks posed by industrially created trans-unsaturated fatty acids in our diet and advocate for regulatory actions on their use in food products. This new understanding of fat processing offers potential therapeutic targets for conditions like ASCVD, non-alcoholic fatty liver disease, obesity, diabetes, peripheral neuropathy, and neurodegeneration.
It’s well-known that excess cholesterol contributes to the formation of plaques in arteries, which can result in serious health issues like stroke, arterial disease, and heart attacks. This understanding has led to numerous public health campaigns focusing on cholesterol management. Thanks to this effort, cholesterol-lowering medications known as statins have been developed, along with lifestyle changes involving diet and exercise. However, might there be more factors at play beyond just cholesterol?
New discoveries from the Salk Institute indicate that a different type of lipid, called sphingolipids, also plays a role in the formation of arterial plaques and the progression of ASCVD. In a study involving mice on high-fat diets without added cholesterol, researchers examined the movement of these fats through the body and established that high trans fat consumption leads to ASCVD progression through the incorporation of trans fats into ceramides and other sphingolipids. This highlights an additional aspect of cardiovascular disease alongside the previously acknowledged effects of cholesterol.
The results of this research were published in Cell Metabolism on November 14, 2024, paving the way for new potential drug targets to treat these conditions and avert critical health crises such as strokes or heart attacks.
“Dietary fat is a significant part of our nutrition, and trans fats have been linked to increased heart disease risk. We aimed to dissect the biological processes that elevate this risk,” explained Christian Metallo, a senior author and professor at Salk. “Numerous studies have focused on how trans fats contribute to cardiovascular issues, typically returning to cholesterol as the primary concern. We took a novel approach, removing cholesterol as a variable, which led us to discover a specific enzyme and pathway relevant to cardiovascular health that could be targeted for therapeutic purposes.”
When dietary fats enter the body, they undergo processing into different types of lipids such as triglycerides, phospholipids, cholesterol, or sphingolipids. Lipoproteins like HDL, LDL, and VLDL are then responsible for transporting these lipids through the bloodstream.
Sphingolipids serve as important indicators for various diseases, including ASCVD, non-alcoholic fatty liver disease, obesity, diabetes, peripheral neuropathy, and neurodegeneration. Nevertheless, the specific mechanisms by which different dietary fats integrate into sphingolipids and contribute to ASCVD remain unclear.
The researchers sought to determine how trans fats are processed into sphingolipids and whether these newly formed sphingolipids influence the release of lipoproteins such as VLDL, which when excessive, can lead to artery blockages.
According to Metallo, the processing of dietary fats often hinges on the specific proteins that metabolize them. Thus, it was crucial for the Salk team to first examine the metabolic framework involved in sphingolipid synthesis. They began their investigations with a protein named SPT, which regulates the production of sphingolipids from fatty acids and amino acids like serine.
The researchers hypothesized that trans fats might be integrated into sphingolipids via SPT, subsequently leading to increased lipoprotein release into the bloodstream—thereby contributing to ASCVD.
To explore their hypothesis, they compared the processing of two types of fats: cis fats and trans fats. The distinction between the two lies in the positioning of hydrogen atoms; cis fats, typically found in natural foods like fish and walnuts, contain a kink in their structure due to two adjacent hydrogen atoms. In contrast, trans fats, commonly found in processed foods such as margarine or deep-fried items, have a straight-chain configuration caused by opposing hydrogen atoms. This structural kink in cis fats prevents them from being tightly packed, making them less likely to cause blockages.
The researchers employed a combination of dietary manipulation in mice, metabolic tracing, pharmacological interventions, and physiological assessments to investigate the relationship between trans fats, sphingolipids, and ASCVD.
“Our findings showed that trans fats incorporated through SPT led to greater lipoprotein secretion from the liver, which facilitated the development of atherosclerotic plaques,” stated first author Jivani Gengatharan, a postdoctoral researcher in Metallo’s lab. “This underscores the role of sphingolipid metabolism as a crucial factor in the progression of cardiovascular diseases linked to specific dietary fats.”
Starting their investigations with cells grown in Petri dishes, the team assessed whether SPT favored the metabolism of trans or cis fats, discovering a preference for trans fats. Furthermore, SPT’s inclination toward processing trans fats was leading to increased sphingolipid secretion that could contribute to plaque formation.
Next, the researchers shifted their focus to mice, with Gengatharan designing two identical diets—one rich in trans fats and the other in cis fats, both with minimal cholesterol—feeding them to mice over a 16-week period. Ultimately, mice on the high trans fat diet produced sphingolipids derived from trans fats, which in turn enhanced VLDL secretion from the liver into the bloodstream. This process accelerated the accumulation of atherosclerotic plaques and resulted in fatty liver conditions and insulin irregularities. In contrast, mice on the high cis fat diet experienced shorter-term, less severe outcomes like weight gain.
To further investigate the effects, the team inhibited SPT activity to assess whether this could counteract the adverse impacts of trans fats in mice, discovering that reduced SPT activity did indeed diminish trans fat-induced atherosclerosis. As Metallo notes, these findings position the sphingolipid synthesis pathway through SPT as a significant target for developing ASCVD treatments in the future.
“As we improve our understanding of these diverse molecules circulating in our bodies and their metabolic pathways, we could make significant progress toward personalized medicine,” Metallo elaborates. “For now, I advise moderation—everyone has unique dietary habits, genetic factors, and predispositions. As we explore these elements, we will enhance our understanding and broaden treatment possibilities in the future.”
One particular subunit of SPT caught the researchers’ attention for future studies, as the team suspects it may play a role in selectively releasing harmful lipids from the liver. With SPT in focus, the researchers aspire to see novel non-statin drug development aimed at the management and prevention of cardiovascular diseases.
Despite the World Health Organization (WHO) announcing a goal to eliminate trans fats from food supplies by the end of 2023, nearly 4 billion individuals remain at risk in 2024 due to non-compliance with WHO recommendations in several nations. The research team hopes their findings will positively impact the lives of those still at risk.
Other contributors to this study include Zoya Chih, Maureen Ruchhoeft, and Ethan Ashley from Salk; Michal Handzlik and Courtney Green from Salk and UC San Diego; Patrick Secrest and Philip Gordts from UC San Diego; and Martina Wallace from University College Dublin.
This research was funded by the National Institutes of Health (R01CA234245), the Aileen S. Andrew Foundation, and the Mary K. Chapman Foundation.
