In previous posts, we’ve established the role of saturated fats in elevating LDL cholesterol as well as the causal role of elevated LDL cholesterol in heart disease, contradicting false claims made by a number of journalists, bloggers, YouTubers, and crank doctors that have tried to confuse the public regarding the relationship between saturated fats, LDL cholesterol, and heart disease. Using GPT-4o, we now explore the precise mechanisms by which saturated fats in the diet elevate LDL cholesterol.
Q1: What are the mechanism by which saturated fat elevates LDL cholesterol?
Saturated fat elevates low-density lipoprotein (LDL) cholesterol through multiple mechanisms that affect lipid metabolism, hepatic function, and lipoprotein clearance. Below is a detailed explanation of the primary mechanisms:
1. Decreased LDL Receptor Activity
- Mechanism: Saturated fats, particularly myristic and palmitic acids, reduce the expression of LDL receptors on hepatocyte surfaces.
- Molecular Pathway:
- Saturated fats suppress the activity of the Sterol Regulatory Element-Binding Protein 2 (SREBP-2), a transcription factor that upregulates LDL receptor expression.
- With lower SREBP-2 activity, the liver produces fewer LDL receptors, reducing the clearance of LDL particles from circulation.
- Impact: The reduced uptake of LDL cholesterol by the liver leads to elevated plasma LDL levels.
2. Increased Cholesterol Synthesis
- Mechanism: Saturated fats stimulate hepatic cholesterol production by increasing the activity of HMG-CoA reductase, the enzyme responsible for converting HMG-CoA to mevalonate, a precursor of cholesterol.
- Molecular Pathway:
- Saturated fats reduce feedback inhibition of HMG-CoA reductase, even when cholesterol levels are high, disrupting the normal homeostatic regulation of cholesterol synthesis.
- Impact: The liver produces more cholesterol, which is packaged into VLDL particles and released into the bloodstream. These VLDL particles are later converted into LDL.
3. Altered Lipoprotein Composition and Particle Size
- Mechanism: Saturated fats influence the structure and composition of lipoproteins.
- Changes in Composition:
- LDL particles enriched with saturated fatty acids contain more cholesterol esters, making them denser and smaller.
- Small, dense LDL particles are less easily cleared by LDL receptors and are more susceptible to oxidation.
- Impact: Oxidized LDL is highly atherogenic, as it is readily taken up by macrophages in arterial walls, contributing to foam cell formation and atherosclerotic plaque development.
4. Reduced Bile Acid Synthesis
- Mechanism: Saturated fats reduce the activity of enzymes involved in converting cholesterol into bile acids, such as cholesterol 7α-hydroxylase.
- Impact:
- A smaller proportion of cholesterol is diverted to bile acid synthesis and excretion.
- The remaining cholesterol pool in the liver increases, leading to greater secretion of cholesterol into lipoproteins like VLDL.
5. Impaired Lipoprotein Clearance
- Mechanism: Saturated fats interfere with enzymes and processes involved in clearing triglyceride-rich and cholesterol-rich lipoproteins.
- Enzymatic Effects:
- Lipoprotein lipase (LPL): Reduced activity decreases the hydrolysis of triglycerides in VLDL particles, prolonging their presence in the bloodstream.
- Hepatic lipase: Altered activity affects the remodeling of LDL particles, reducing their clearance.
- Impact: VLDL particles persist longer and are more likely to be converted into LDL, increasing the circulating pool of LDL cholesterol.
6. Reduced Efficiency of Reverse Cholesterol Transport
- Mechanism: Saturated fats may impair the function of high-density lipoprotein (HDL), which is critical for reverse cholesterol transport.
- Pathway:
- Saturated fats reduce the activity of ABCA1 (ATP-binding cassette transporter A1), a protein responsible for transferring cholesterol from cells to HDL.
- This impairs the ability of HDL to deliver excess cholesterol back to the liver for excretion.
- Impact: Less cholesterol is cleared from peripheral tissues, leading to an accumulation of circulating LDL cholesterol.
7. Pro-inflammatory and Oxidative Effects
- Mechanism: Saturated fats can promote low-grade systemic inflammation and oxidative stress, which indirectly influences lipoprotein metabolism.
- Pathway:
- Inflammatory cytokines such as IL-6 and TNF-α disrupt hepatic lipid metabolism.
- Oxidative stress leads to the formation of oxidized LDL, which is not recognized by LDL receptors but is taken up by scavenger receptors on macrophages.
- Impact: Inflammatory and oxidative processes exacerbate atherogenesis and prolong the residence time of LDL in the bloodstream.
8. Fatty Acid-Specific Effects
- Lauric, myristic, and palmitic acids: These fatty acids are most effective at raising LDL cholesterol because they directly influence cholesterol metabolism and LDL receptor activity.
- Stearic acid: While a saturated fat, it has a neutral effect on LDL cholesterol because it is rapidly converted to oleic acid (a monounsaturated fat) in the body.
9. Effects on Lipid Transfer Proteins
- Mechanism: Saturated fats affect the activity of cholesteryl ester transfer protein (CETP), which transfers cholesterol esters between lipoproteins.
- Impact:
- Increased CETP activity can reduce HDL cholesterol while transferring cholesterol to LDL particles, amplifying the rise in LDL cholesterol.
10. Interference with Gut Microbiota
- Mechanism: Saturated fat intake alters gut microbiota composition, leading to increased production of lipopolysaccharides (LPS) that promote systemic inflammation.
- Impact: Inflammation affects hepatic lipid metabolism, indirectly contributing to elevated LDL cholesterol levels.
Summary of Impacts
Saturated fats elevate LDL cholesterol by:
- Reducing LDL receptor activity and clearance.
- Increasing cholesterol synthesis in the liver.
- Altering lipoprotein composition to create smaller, denser LDL particles.
- Reducing bile acid synthesis and excretion.
- Impairing reverse cholesterol transport.
- Promoting inflammation and oxidative stress.
These mechanisms collectively lead to higher circulating LDL levels, increased atherogenicity, and greater cardiovascular risk.
Q2: Explain this in layman’s terms.
Here’s a simplified explanation of how eating saturated fat can raise “bad” LDL cholesterol in your body:
1. Saturated Fat Slows Cholesterol Removal
- Your liver has special “receptors” that grab LDL cholesterol from your blood and clear it out.
- Saturated fat reduces the number of these receptors, so less LDL is removed. The leftover LDL stays in your blood and builds up.
2. Your Body Makes More Cholesterol
- Your liver also produces cholesterol naturally. Saturated fat can “turn on” the process that makes cholesterol in the liver, even if your body already has enough.
- This adds more cholesterol to your bloodstream.
3. Saturated Fat Changes LDL Particles
- Saturated fat changes the shape and size of LDL particles, making them smaller and denser.
- These smaller LDL particles are worse for your arteries because they can get stuck in the walls of blood vessels more easily and are more likely to trigger problems like plaque buildup.
4. Less Cholesterol is Broken Down
- Normally, your liver uses cholesterol to make bile, which helps digest food and gets rid of excess cholesterol.
- Saturated fat slows down this process, so more cholesterol stays in your body instead of being excreted.
5. Fats Stay in the Bloodstream Longer
- Saturated fat makes it harder for your body to break down and clear out fats (like LDL cholesterol) that are already in your blood.
- This means LDL levels keep rising over time.
6. Inflammation and Damage
- Eating too much saturated fat can cause low-level inflammation in your body.
- Inflammation makes it easier for LDL cholesterol to stick to the walls of your arteries, where it can get damaged and turn into “oxidized LDL.”
- This damaged cholesterol is more harmful and can start the process of artery clogging.
7. Different Fats, Different Effects
- Not all saturated fats are the same. Some (like those in butter or fatty meats) raise LDL cholesterol more than others.
- Fats like those in chocolate or certain plants (like stearic acid in cocoa butter) have little or no effect on LDL.
Why This Matters:
When LDL cholesterol builds up, it can stick to the walls of your arteries, forming fatty deposits (called plaques). Over time, this can narrow your arteries and make it harder for blood to flow. If a plaque breaks open, it can cause a heart attack or stroke.
So, eating too much saturated fat can set off a chain reaction: more LDL cholesterol, more artery buildup, and higher risk of heart disease. That’s why doctors often recommend limiting foods high in saturated fat, like fatty cuts of meat, butter, and full-fat dairy products.
We have now learned that saturated fats raise LDL cholesterol, that LDL cholesterol plays a causal role in heart disease, and the mechanisms by which consuming saturated fats raises LDL cholesterol. These findings directly contradict many of the false claims by a number of journalisms, bloggers, YouTubers, and quack doctors who actively promote unhealthy eating patterns for their own personal gain.
One such journalist is Gary Taubes. Our next post takes in-depth look at the claims he makes in one of his books: “Carbs, Fat, and Cherry-Picked Facts: A Critical Review of Gary Taubes’s Good Calories, Bad Calories”
