Take a Precise Approach to Cholesterol.
Contemporary cholesterol research focuses on agents and antibodies that can lower the production of cholesterol, sequester bile acids, and increase cholesterol excretion through bowel movements. Yet, the understanding of why certain people get high cholesterol is still widely unclear. One of the most compelling reasons?
Your genes.
Before we go too in depth, let’s begin with a quick primer lesson on cholesterol. Your CGM doc will likely walk you through a similar lesson upon reviewing these measurements.
Vocabulary:
Lipid: The term lipids encompasses a broad group of naturally-occurring molecules comprised of fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. When we order your cholesterol, we actually order a lipid panel.
Lipoprotein: a term for a lipid-binding protein molecule that carries these particles in the blood stream (fats can’t travel on their own through blood, which is water-based). Lipoproteins are categorized by their density. For example, LDL is “low density lipoprotein.”
Cholesterol: a type of lipid. Specifically, cholesterol is a type of fat that is made up of four interlocked rings of carbon called a sterol. Its steroid structure comes into play when cholesterol acts as the building block for steroid hormones like estrogen and testosterone.
The Lipid Panel.
When we order a conventional lipid panel, we receive the following measurements.
Total cholesterol: the total amount of cholesterol quantified in the sample.
Low-density lipoprotein cholesterol (LDL-C): LDL-C forms in the blood when very low-density lipoprotein (VLDL) loses some fat (triglycerides) and becomes denser. It’s removed by the liver and travels to peripheral tissues and organs to deposit cholesterol. LDL is commonly referred to as “bad” cholesterol because of its propensity to deposit this cholesterol on arterial walls. This deposition is “pro-atherogenic” in that it makes it more likely for us to develop atherosclerotic plaques.
High-density lipoprotein cholesterol (HDL-C): HDL particles help remove excess cholesterol from the blood and arterial wall by bringing it back to the liver, where it can become bile that then gets excreted through feces, or be taken to the adrenal glands, testes, and ovaries for hormone production. Cholesterol carried by HDL particles is revered as “good” due to the fact that it’s being removed from arterial walls, thus decreasing athero risk.
Triglycerides (TG): These are the fats you eat in your diet and those that are stored in adipose (fat) tissue. TG’s are formed from a combination of a compound called glycerol and three fatty acids. Dietary triglycerides are digested and absorbed in the small intestine. The liver can also produce triglycerides from sugars and other fats in the presence of excess carbohydrates or a positive energy balance (eating more than you burn).
At CGM, we preferentially order what’s called an “Advanced Lipid Panel,” which delves deeper into the particulars of the conventional lipid panel to give us a break down of lipoproteins. These lipoproteins are considerably more descriptive of one’s cholesterol metabolism. Additionally, we can identify the presence of genetic causes of high cholesterol, such as elevated Lipoprotein(a), which is only measured through these advanced panels.
Genomic Causes of High Cholesterol.
When working with patients towards goals of lowering their cholesterol, CGM docs may investigate their genomics to identify areas of pressure or inefficiency in cholesterol metabolism. We can then use natural agents specifically targeted for regulating the expression of that specific gene and enzyme.
Genes associated with cholesterol metabolism include:
LDLR:
The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in the uptake of lipid molecules into the cell. Once inside the cell, cholesterol becomes liberated from LDL, and its presence inhibits the synthesis of additional cholesterol by repressing the rate-limiting step of cholesterol fabrication, making LDLR expression an important determinant of cholesterol synthesis. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Less severe variants can cause elevated total cholesterol.
APOB:
The APOB gene provides instructions for making two versions of the apolipoprotein B protein: ApoB-48, and ApoB-100. ApoB-100 is the protein ‘tag’ found on LDL, while ApoB-48 is for chylomicrons (triglyceride-rich lipoproteins that are the ‘fed’ version of VLDL produced in the intestine from dietary lipids). Variants in this gene can increase levels of ApoB, which correlate negatively with cardiovascular health.
LPL:
LPL encodes lipoprotein lipase, an enzyme expressed in heart, muscle, and fat tissue. LPL functions on the capillary endothelium to hydrolyze Very Low Density Lipoprotein (VLDL) to Intermediate Density Lipoprotein (IDL) to deliver free fatty acids to tissue. Severe mutations can cause LPL deficiency, which results in type 1 hyperlipoproteinemia, while less extreme variants are linked to many disorders of lipoprotein metabolism and elevated triglycerides.
PCSK9:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme coded by the PCSK9 gene. It is expressed in liver, intestine and kidney tissues, and controls the number of low-density lipoprotein receptors expressed on the surface of the cell. PCSK9 breaks down the LDL receptors before they reach the cell surface, reducing the amount of LDL that can be internalized. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia, and also reduced LDL-cholesterol.
CETP:
Cholesterol ester transfer protein is a protein found on HDL particles that allows for the attachment of lipids to lipoproteins. Most of the time, CETP trades a triglyceride for a cholesterol component, or vice versa. In people born with CETP deficiencies, we see elevated HDL and low LDL, signifying to us that lower CETP activity exhibits beneficial effects on the lipid profile. Variants in CETP can cause an overactive CETP enzyme, resulting in higher LDL, and lower HDL.
ALPI:
ALPI encodes for the intestinal sibling of the enzyme family of alkaline phosphatases. There are least four distinct but related isoenzymes: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The intestinal alkaline phosphatase enzyme is involved in the regulation of lipid absorption in the gut. The lowest levels of IAP exist in Blood Type A, and are associated with increased cardiovascular risk.
If you have high cholesterol or a family history of heart disease, you may want to work with your CGM doc to identify these genomic variants. There are many more genes relevant to modulating one’s cholesterol than those discussed above, and your CGM doc will take the time to go through each one in analyzing your case.
As with any health concern, out of range values can be scary! Working with your doc to pinpoint exactly where the issue lies allows us to be precise in our approach to lowering your cholesterol while avoiding unnecessary side effects and minimize your long-term risk.
Dr. Emily D’Adamo
January, 2023.