Want to lower cholesterol? It’s a worthy goal.
High LDL-C is one of the major risk factors for heart disease.
When approaching a cholesterol lowering plan of attack, it may be helpful to think of how the popular drugs on the market achieve lower cholesterol. Statins famously stop the body from making cholesterol in the liver. Zetia works by stopping absorption of cholesterol. Finally, PCSK9 Inhibitors work to lower cholesterol by helping the body take more out of circulation. That’s right, the liver plays a role in making, but also in clearing cholesterol from our system.
In other words, the level of cholesterol in your blood doesn’t just depend on how much cholesterol your body makes. Cholesterol clearance matters too. The main genes known to affect cholesterol clearance are PCSK9 and LDLR, as well as the APOB gene. These control the number of low-density lipoprotein (LDL) receptors, their activity, and overall cholesterol clearance.
So, how does cholesterol clearance work and what should you be looking for in your genome? Here, I offer a quick overview of the genes behind the scenes and five quick hacks to improve cholesterol clearance.
How does cholesterol clearance work?
To get around the body, cholesterol hitches a ride on low-density lipoprotein (LDL). This is the main transport vehicle for cholesterol, and the more of these transporters in the blood, the more likely they will make a “wrong turn” and deliver cholesterol into the artery wall where the long process of heart disease begins. This is why there’s so much focus on keeping LDL-cholesterol levels low – LDL alone doesn’t cause heart disease, but it is a necessary step in the progression of the disease.
Turns out our body has a natural process for drawing down on LDL levels and keeping them in check.
LDL receptors on the surface of cells bind to LDL particles, whisk them into the cell, break down the protein component and free the cholesterol for use, storage, or removal. When your cells are actively taking up a lot of cholesterol from blood, they slow down their own cholesterol production processes, helping to keep cholesterol levels stable.
LDLR and cholesterol clearance
Assuming everything else is working as it should, the more active LDLR, the more LDL receptors you should have on your cells. This translates to faster clearance of LDL-cholesterol from circulation and lower LDL-C for you.
In contrast, reduced LDLR activity reduces the number or activity of LDL receptors on your cells. This, in turn, reduces your ability to remove LDL cholesterol from your blood, which means LDL-C levels go up.
Geneticists have identified more than 2,000 mutations in the LDLR gene associated with familial hypercholesterolemia (FH). Some affect how many receptors you have, and some disrupt the receptors’ ability to remove LDL cholesterol from the blood.
As with most genetic conditions, the majority of those with FH have just one altered copy of LDLR. If you’re in this position, you’re thought to have an increased risk of early onset of heart disease, usually around the age of forty or fifty. If someone inherits two altered copies of LDLR, the effects are more severe, with hypercholesterolemia typically making itself known in childhood.
In one recent study, the following six variations were identified among Mexican adults with FH: 2
- -139delCTCCCCCTGC (a new variant located in the promoter region)
- Leu759Serfs*6 (the most frequently identified variant, found in 43.7% of the alleles).
LDL receptors are not just governed by the LDLR gene, however. One other gene, identified in 2001, called PCSK9, also has a big effect on cholesterol clearance.
PCSK9 and cholesterol clearance
After LDL receptors transport LDL-C into the cells, these receptors get recycled and head back to the cell surface to keep on trucking. That is, unless they encounter a protein called PCSK9.
PCSK9 is the gene that provides instructions for the creation of PCSK9. This protein degrades LDL receptors and reduces the number of these receptors that make it back to the surface of cells.3
So, even if you have two functional copies of LDLR, an over-active PCSK9 gene can still lead to familial hypercholesterolemia. In folks with FH, the alteration in the PCSK9 gene is said to be a ‘gain-of-function’ mutation, because it ramps up the activity of the gene.
Again, the greater the activity of PCSK9, the fewer LDL receptors on cells, and the lower the uptake of LDL cholesterol.
In contrast, if you happen to have a variation in the PCSK9 gene that reduces its activity, your body will make very little PCSK9 protein. This means you’ll have way more receptors ready to sequester LDL and keep blood cholesterol levels in check.
Now, what about that third gene, APOB?
APOB and cholesterol clearance
APOB mutations are currently considered a rare cause of FH, but some researchers have suggested that more thorough screening may reveal a greater role for such mutations in the disease.4
The APOB gene codes for a short protein called apolipoprotein B-48 and a longer protein called apolipoprotein B-100. The former is produced in the intestines and helps transport fat and cholesterol into the blood (as well as fat soluble nutrients!). The longer apolipoprotein B-100 is produced in the liver. This version is a building block of low- to very-low-density lipoproteins and allows these to attach to the LDL receptors on the surface of cells. Apolipoprotein B-100 is particularly fond of liver cells (hepatocytes), which is where most cholesterol gets processed.
FH is known to be caused by more than 100 mutations in APOB. These mutations all affect apolipoprotein B-100, which makes it hard for LDL to attach to LDL receptors. This means less LDL-cholesterol gets removed from the blood, resulting in very high blood cholesterol.
As with LDLR mutations in FH, most folks with an APOB mutation inherit at least one functional copy of the gene, meaning they create some normal apolipoprotein B-100. Still, these mutations are associated with an increased risk of early heart disease. In cases where a person inherits two faulty copies of the gene, FH usually arises in childhood and is more severe.
So, assuming you have one or more of these mutations, what can you do to support cholesterol clearance and keep LDL-C in check?
How to support cholesterol clearance
Lifestyle and dietary changes can help to keep cholesterol levels in check, but these are unlikely to be sufficient in cases of homozygous mutations causing FH. Even in heterozygous FH, it’s a struggle to keep LDL-C low.
This is why most folks with a genetic disposition for high cholesterol are prescribed cholesterol-lowering medications like statins. 5 Statins don’t always help, however. They may be insufficient to lower LDL-C themselves or may cause intolerable side effects.
Unsurprisingly, since PCSK9 was discovered in 2001, drug researchers have been working hard to develop inhibitors of the protein. Two PCSK9 inhibitors, alirocumab (Praluent) and evolocumab (Repatha), are now approved for use in FH. These offer a relatively novel way to increase the number of LDL receptors on cells and, thus, cholesterol clearance.
5 ways to enhance cholesterol clearance
Recent research suggests several potential hacks to improve cholesterol clearance, based on the three genes mentioned. For example, fasting seems to reduce plasma PCSK9 levels. Omega-3 fatty acids may also reduce PCSK9 and the expression of mRNA PCSK9 in the liver. In contrast, dietary fructose appears to increase mRNA PCSK9 expression and levels of the protein in blood.10
Another study recently found that Lunasin, a polypeptide found in soy, also decreases the expression of PCSK9. This may explain one mechanism by which soy lowers cholesterol.11
An analysis of a dozen papers also concluded that berberine could offer an alternative option for individuals who are intolerant to statins or who have other reservations about statin therapy. Why? Because this compound is thought to increase the number of LDL receptors on liver cells and decrease PCSK9 levels.12
Berberine is a compound found in goldenseal root, huanglin (a Traditional Chinese Medicine), and in other plants of the genus Berberis. The analysis of research so far found that berberine, “has a beneficial effect on low-density lipoprotein (reductions ranging from approximately 20 to 50 mg/dL) and triglycerides (reductions ranging from approximately 25 to 55 mg/dL).”
It’s important to note, though, that berberine may interact with other drugs as it inhibits cytochrome P450 (CYP) 2D6, 2C9, and 3A4. Berberine is also poorly absorbed and quickly metabolized. Still, in one study, 32 people given 500 mg of berberine twice daily for three months had a 25% reduction in LDL, 35% reduction in triglycerides, and a 29% reduction in total cholesterol. These people weren’t taking any other lipid-lowering drugs at the time.13
Putting it all into action
So, how about some quick hacks to lower LDL-cholesterol by improving cholesterol clearance?
- Increase omega-3 intake
- Reduce fructose intake (as a sweetener, primarily)
- Fast intermittently
- Eat soy
- Consider a berberine supplement.
Preliminary research has also found that alginate oligosaccharide (AOS) increased LDLR expression and the uptake of LDL in liver cells in a dose- and time-dependent manner. This appears to be because AOS enhances the activity of sterol-responsive element binding protein-2 (SREBP-2), which is essential for LDLR gene expression. PCSK9 mediates this enhancement, and researchers have found that AOS also reduced levels of PCSK9, further supporting reduced blood cholesterol levels.14 Unfortunately, there aren’t any AOS supplements commercially available currently; if you find one, let us know.
And, as always, it’s a good idea to give your liver some love if you want to reduce blood cholesterol. LDL receptors are pretty much everywhere in your body but are especially abundant in the liver. So, keep your alcohol intake low and consider taking a milk thistle supplement every so often. And, as always, keep a check on your intake of saturated fats.
Mutations in LDLR, PCSK9, and APOB cause the autosomal dominant disorder, familial hypercholesterolemia (FH). Some folks with a mutation in LDLR have pretty normal LDL-C levels, while others have very high levels. Environmental effects and modifying genes including PCSK9 and APOB also contribute to the risk of FH.
FH is characterized by very high levels of cholesterol and an increased risk of heart disease, heart attack, stroke, and early death. Taking steps to reduce LDL-cholesterol, through lifestyle, diet, supplements, and medications is vital to reduce health risks.