Photo credit: www.sciencedaily.com

Unraveling the Impact of Trans Fats on Heart Disease

Researchers from the Salk Institute have made significant strides in understanding how trans fats contribute to atherosclerotic cardiovascular disease (ASCVD) through mouse model studies. Their findings shed light on the mechanisms by which industrially produced trans-unsaturated fatty acids in food exacerbate ASCVD and call for regulatory measures to limit their use. This research not only enhances our understanding of fat metabolism but also opens new potential therapeutic avenues for conditions such as ASCVD, non-alcoholic fatty liver disease, obesity, diabetes, peripheral neuropathy, and neurodegeneration.

Cholesterol has long been the focus of cardiovascular health discussions due to its role in forming artery-clogging plaques that can lead to serious health issues like strokes and heart attacks. This focus has catalyzed the development of cholesterol-lowering medications, particularly statins, and has spurred lifestyle changes in dietary and exercise habits. However, emerging research suggests that the landscape of cardiovascular health may involve more than just cholesterol.

In a groundbreaking study, Salk Institute scientists identified that another class of lipids, known as sphingolipids, also plays a significant role in the formation of arterial plaques and the progression of ASCVD. By conducting a longitudinal examination of mice on high-fat diets devoid of additional cholesterol, the team discovered that the incorporation of trans fats into sphingolipids, particularly ceramides, exacerbates the progression of ASCVD. This revelation broadens the understanding of cardiovascular disease beyond its traditional cholesterol-centric view.

Published in Cell Metabolism on November 14, 2024, these findings highlight new potential drug targets to combat ASCVD and related health crises.

“Dietary fats are a fundamental part of our food intake, and trans fats are particularly harmful in relation to heart disease. By investigating this phenomenon, we aimed to reveal the biological pathways that increase our risk,” explains Christian Metallo, the study’s senior author and a professor at Salk. “While previous studies have looked at the role of trans fats in cardiovascular risk, they often returned to cholesterol. Our research focused directly on the role of trans fats, and we identified a specific enzyme and metabolic pathway that could be targeted for therapeutic intervention.”

Upon entering the body, dietary fats undergo a complex sorting and processing mechanism, transforming into various compounds known as lipids, including triglycerides, phospholipids, cholesterol, and sphingolipids. These lipids are transported through the bloodstream by lipoproteins such as HDL, LDL, and VLDL.

Sphingolipids are gaining recognition as significant biomarkers for various diseases, including ASCVD and obesity. However, the precise interaction between different types of dietary fats and the formation of sphingolipids in relation to ASCVD remains to be fully elucidated.

The researchers specifically aimed to understand how trans fats, upon processing into sphingolipids, might be influencing atherosclerotic plaque development. They questioned whether sphingolipids produced in the liver could affect the release of lipoproteins like VLDL into the bloodstream, which can lead to arterial blockages when present in excess.

Metallo emphasized the importance of the proteins involved in fat metabolism, particularly a protein called SPT, which regulates sphingolipid production from fat molecules and amino acids such as serine. The team hypothesized that SPT might facilitate the integration of trans fats into sphingolipids, subsequently driving excessive lipoprotein secretion and contributing to ASCVD.

To explore their hypothesis, researchers compared the metabolism of cis fats, found in natural foods, with trans fats, prevalent in processed foods. The distinction lies in the arrangement of hydrogen atoms; cis fats possess a kink in their structure while trans fats have a straight chain. This kink is crucial, as it prevents cis fats from being tightly packed, a property conducive to reducing blockages.

Using a combination of dietary manipulations, metabolic tracing, and pharmacological assessments, the Salk team set out to clarify the relationship between trans fats, sphingolipids, and ASCVD. Their results indicated that trans fats incorporated via SPT led to increased VLDL secretion from the liver, thereby promoting plaque formation.

As the research progressed from lab experiments to in vivo studies, mice were fed high trans fat diets and compared with those on high cis fat diets. After 16 weeks, the mice on a trans fat diet demonstrated an increase in trans fat-derived sphingolipids, resulting in greater VLDL secretion and accelerated atherosclerotic plaque buildup, alongside adverse effects like fatty liver and insulin resistance. Meanwhile, the cis fat group only faced short-term consequences like weight gain.

To assess the potential for mitigating these negative effects, the researchers inhibited SPT activity in their mouse models, discovering that this intervention reduced trans fat-induced atherosclerosis, emphasizing the significance of sphingolipid synthesis through SPT as a therapeutic target for ASCVD.

“Our growing understanding of the various molecules circulating in our bodies and their metabolic pathways is paving the way for personalized medicine,” Metallo remarked. “For now, moderation in dietary intake remains key for maintaining health. Personal genetics and dietary habits should guide individual choices, and as we deepen our understanding, we can refine treatment strategies accordingly.”

Notably, the researchers highlighted a specific subunit of SPT for future investigation, believing it may play a role in selectively releasing harmful lipids from the liver. They anticipate that this focus could lead to new non-statin therapies for managing and preventing cardiovascular diseases.

Despite the World Health Organization’s initiative to eliminate trans fats from global food supplies by 2023, approximately 4 billion people are still at risk as some nations fail to adopt its recommendations. The research team is hopeful that their findings can contribute to improving health outcomes for those at risk.

Co-authors of the study included Zoya Chih, Maureen Ruchhoeft, and Ethan Ashley of Salk; Michal Handzlik and Courtney Green from Salk and UC San Diego; Patrick Secrest and Philip Gordts of UC San Diego; and Martina Wallace from University College Dublin.

The research received support from the National Institutes of Health (R01CA234245), Aileen S. Andrew Foundation, and Mary K. Chapman Foundation.

Source
www.sciencedaily.com