People exposed to PFAS chemicals tend to have higher levels of certain blood fats called cholesterol, which are known to increase the risk of heart disease.
Mechanism
Synthesis from 1 study
PFAS mess up the liver’s ability to break down and get rid of fats and cholesterol, so the liver starts dumping more bad cholesterol into the blood. This buildup can clog arteries over time. Other effects, like making blood clot more easily or slowing thyroid function, may also contribute, but the...
Most probable mechanism
PFAS chemicals enter the liver and interfere with how it processes fats and cholesterol. They turn on a switch called PPARα that makes the liver burn fats in a way that creates harmful stress and damages its energy systems. At the same time, they block other important tools the liver uses to break down fats and remove cholesterol, causing fats and cholesterol to build up inside liver cells. As a result, the liver releases more cholesterol into the blood, raising levels of bad cholesterol, which can clog arteries over time.
PFAS molecules bind to and activate the nuclear receptor PPARα in hepatocytes
Activated PPARα increases expression of ACOX1, driving excessive peroxisomal fatty acid oxidation that generates reactive oxygen species and depletes cellular energy
Oxidative stress and mitochondrial dysfunction impair the liver’s ability to clear lipids and cholesterol
PFAS suppress the expression of NUDT7, reducing acetyl-CoA hydrolase activity and further limiting fatty acid breakdown
PFAS inhibit the expression of HNF4α, reducing transcription of Cyp7A1, the enzyme responsible for converting cholesterol into bile acids
Reduced bile acid synthesis causes cholesterol to accumulate in hepatocytes instead of being excreted
Accumulated hepatic cholesterol is packaged into lipoproteins and secreted into the bloodstream, elevating serum total cholesterol and LDL-C
Less supported by current evidence, but not ruled out
Certain PFAS chemicals bind directly to platelets, causing them to become overactive and stick together more easily, which can lead to blood clots that block arteries.
Long-chain PFAS bind to the GPIbα receptor on platelet surfaces
This binding triggers an influx of calcium ions inside platelets
Calcium activation causes integrin αIIbβ3 to change shape and bind fibrinogen
Fibrinogen cross-links platelets, forming aggregates that increase clotting risk
PFAS interfere with thyroid hormone levels by blocking how the thyroid takes up iodine and how thyroid hormones are transported in the blood, which slows down metabolism and causes fats and cholesterol to build up.
PFAS compete with thyroid hormone for binding to transthyretin, reducing its transport in blood
PFAS inhibit the sodium iodide symporter in thyroid cells, reducing thyroid hormone production
Lower thyroid hormone levels reduce basal metabolic rate and decrease clearance of LDL cholesterol
Evidence from Studies
Supporting (1)
Community contributions welcome
Toxicological Effects and Health Impacts of Per- and Polyfluoroalkyl Substances (PFAS) in Humans
Contradicting (0)
Community contributions welcome
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