Cholesterol and Our Quest to Understand It

Hello Everyone!

Welcome to another edition of the monthly 'Amuse-Bouche' series. Like a morsel compliments of the chef, these small but critical scientific bites are created to stimulate your thinking about health and occasionally provide some comic relief. Prior editions.

Cholesterol: Public Enemy No. 1?

Few topics in medicine generate as much confusion as cholesterol. Because elevated cholesterol is associated with atherosclerosis and heart disease, many people assume cholesterol is universally harmful. In reality, cholesterol is an essential molecule without which human life would not be possible.

Atherosclerosis develops when cholesterol-carrying particles interact with a susceptible artery wall over decades. The debate is no longer whether cholesterol contributes to cardiovascular disease. A more useful question is: How can we preserve healthy arteries over a lifetime, and who is at greatest risk of cholesterol-related disease?

Cholesterol Is Essential For Life 

Cholesterol is a waxy molecule found in every cell of our body and is a key building material. It serves several critical functions:

Building and maintaining cells: Cholesterol is a key component of every cell membrane in the body. It helps cells maintain their shape, controls what enters and exits the cell, and keeps membranes from becoming too stiff or too floppy.

Supporting brain function: About 25% of all the cholesterol in the body is found in the brain, where it's essential for forming connections between nerve cells and maintaining the protective coating around nerve fibers.

Making hormones: Cholesterol is the raw material for  all steroid hormones, including cortisol (stress hormone), estrogen, testosterone, and aldosterone (which regulates blood pressure).

Producing vitamin D: When sunlight hits the skin, cholesterol is converted into vitamin D, which is essential for bone health and other functions.

Aiding digestion: The liver converts cholesterol into bile acids, which act like dish soap in the intestines to emulsify dietary fat, making it water- soluble so it can be absorbed.

Most of the cholesterol in our body is made by the body rather than absorbed from food. The body converts glucose through more than 30 enzymatic steps into cholesterol.

Glucose → Pyruvate → Acetyl-CoA → HMG-CoA → Mevalonate → IPP → Squalene → Lanosterol → Cholesterol

Statins lower cholesterol by blocking HMG-CoA reductase, the enzyme that converts HMG-CoA to mevalonate, reducing cholesterol synthesis.

Types of Cholesterol

Cholesterol cannot move through the bloodstream by itself because it is a waxy molecule that is not soluble in water.  The solution is lipoproteins—tiny spherical particles that package cholesterol inside a shell of proteins and fats. Think of lipoproteins as delivery trucks that carry cholesterol through the bloodstream. The proteins on the outside of these particles act like address labels, telling the particle where to go and allowing it to dock at specific cells.

There are several types of these "delivery trucks," and this is where the "good" and "bad" cholesterol labels come from:

LDL (Low-Density Lipoprotein) — Often Called "Bad Cholesterol" but is actually essential for life.

LDL particles carry cholesterol from the liver to cells throughout the body. Cells that need cholesterol have special "docking stations" called LDL receptors that grab these particles and bring them inside.

HDL (High-Density Lipoprotein) — Often Called "Good Cholesterol"

HDL particles do the opposite job—they act like garbage trucks, picking up excess cholesterol from our tissues and artery walls and carrying it back to the liver for disposal and recycling. This process is called reverse cholesterol transport.

VLDL (Very Low-Density Lipoprotein): Made by the liver, these particles carry triglycerides (another type of fat) to the muscles and fat tissue. As they deliver their cargo, they shrink and eventually become LDL particles.

Avoid The Internal Environment That Promotes Atherosclerosis 

Atherosclerosis is a chronic disease in which cholesterol, inflammatory cells, calcium, and scar tissue accumulate within artery walls, forming plaques that can restrict blood flow or rupture, causing heart attacks and strokes.

Arteries are lined by a thin layer of cells called the endothelium, which acts as a barrier between circulating cholesterol and the vessel wall. High blood pressure, smoking, diabetes, excess visceral fat, sleep apnea, chronic inflammation, and unstable blood sugar can damage this barrier. As endothelial dysfunction develops, cholesterol particles are more likely to enter and become trapped within the artery wall.

The Cholesterol-Cardiovascular Disease Connection

Cardiovascular disease is highly prevalent and the leading cause of morbidity and mortality in the US. About 30-50% of people who should be on a lipid-lowering medication are not on medication, and those that are on medication are not at goal. 

Studies have consistently shown that for every 39 mg/dL reduction in LDL cholesterol, the risk of heart attack and stroke drops by about 20-25%.

Those with genes allowing high cholesterol at an early age have more heart attacks and strokes compared to those whose families naturally have lower levels. These observations provide an important insight: cardiovascular risk depends on cumulative exposure over decades. The longer arteries are exposed to elevated levels of cholesterol, the greater the likelihood of plaque formation.

Cholesterol Tests and Target Levels

For most asymptomatic adults, a standard lipid panel, ApoB, Lipoprotein(a), blood pressure assessment, and selective use of coronary calcium scoring along with family history, provide most of the information needed to guide prevention. Not everyone needs all these tests.

• LDL cholesterol (LDL-C)

• Triglycerides

• HDL

• Apolipoprotein B

• Lipoprotein(a)

• High-sensitivity C-reactive protein (hsCRP) 

ApoB is a very informative lipid-related marker because it measures the number of atherogenic particles.

Lipoprotein(a), or Lp(a), is largely inherited and should generally be measured at least once. It indicates genetic risk.

High-sensitivity C-reactive protein (hsCRP) is a blood test that indicates inflammation.

Coronary Calcium CT Scan shows plaque with calcium but not soft plaque which has not calcified yet. Coronary calcium estimates accumulated damage.

Triglycerides are stored fat made from carbs and fat, and are used to transport energy. They are reported in the lipid panel but are not cholesterol.

LDL-C (Normal <100 mg/dl) and lipoprotein particle targets depend on risk factors.

Insulin Resistance and Type 2 Diabetes 

Sometimes we see low LDL-C and high ApoB numbers. Usually triglycerides are elevated and HDL is low in this scenario — the classic pattern of insulin resistance and type 2 Diabetes. In this setting, LDL particles are remodeled into a smaller, denser form of LDL that is more prone to cause atherosclerosis - more likely to penetrate the artery wall, and clear more slowly from circulation. A patient with triglycerides of 175, HDL of 38, and a normal LDL cholesterol of 100 mg/dL may look reassuring on a standard lipid panel — and yet have a substantially higher atherosclerosis risk than their LDL-C suggests. 

What Affects Cholesterol Levels

Cholesterol levels are influenced by a combination of factors.

Factors We Can't Control

Genetics: Some people inherit genes that cause their bodies to produce too much cholesterol or clear it too slowly. In these individuals, heart disease can occur early in life and they need to be treated aggressively and at an earlier age.

Age and sex: Cholesterol levels tend to rise with age. Before menopause, women typically have lower LDL levels than men of the same age, but after menopause, women's LDL levels often increase.

Factors We Can Control

Diet: What you eat has a significant impact. The most important dietary factors are cutting down unhealthy fat and hydrogenated oils like palm oils in processed meat, packaged shelf-stable foods, store-bought desserts and ice-cream. The second is cutting down refined and simple sugars. 

Other dietary strategies that help include:

• Eating more soluble fiber, which can reduce LDL by 5-10%

• Following a Mediterranean-style diet, which emphasizes vegetables, fruits, legumes, nuts, olive oil, and fish can reduce LDL by 10-15 %

Physical activity: Regular exercise can raise HDL cholesterol and lower LDL by 5-10%. Current guidelines recommend at least 150 minutes of moderate-intensity aerobic activity per week.

Weight: Losing 5-10% of body weight in overweight individuals typically reduces LDL cholesterol by 5-8% and triglycerides by 20%, while raising HDL.

Smoking: Quitting smoking raises HDL cholesterol by 5-10% within weeks and substantially reduces cardiovascular risk.

What About Medications

For many people, lifestyle changes alone aren't sufficient, especially those with genetic predisposition or established heart disease. 

Medications act at different points in the pathway, but they share a common goal: reducing exposure of the artery wall to atherosclerosis causing particles.

Statins have the strongest evidence base. Statins (e.g. atorvastatin, rosuvastatin, simvastatin) entered the foray in the early 1990s and they can reduce LDL by 30-55% and have been proven to reduce heart attacks, strokes, and deaths. Statins are used to prevent cardiovascular disease-associated morbidity and mortality because of their positive effects on lipid profiles as well as anti-inflammatory and other plaque-stabilization effects.

Ezetimibe blocks cholesterol absorption in the intestine and can reduce LDL by an additional 15-20% when added to a statin.

PCSK9 inhibitors (like evolocumab and alirocumab) and Inclisiran are injectable medications that help the  liver remove more LDL from the blood. They can reduce LDL by 50-60% and are typically used for people who can't reach their goals with statins alone.

Bempedoic acid works similarly to statins but is only activated in the liver, not in muscles, potentially reducing muscle-related side effects.

Statin Trials

The 2008 JUPITER trial enrolled 17,802 apparently healthy adults with elevated high-sensitivity C-reactive protein (≥2.0 mg/L) but low LDL cholesterol (<130 mg/dL). The trial achieved a median 50% reduction in LDL cholesterol and showed that patients who reached LDL-C <50 mg/dL experienced a 65% reduction in cardiovascular events, demonstrating that the magnitude of cholesterol lowering directly determined clinical benefit. 

Compared with placebo, over 1.9 years rosuvastatin reduced:

Heart attacks by 54%

Strokes by 48%

Major cardiovascular events by 44%

Risk of dying from any cause by 20%

The  2022 systematic review for the U.S. Preventive Services Task Force by Roger Chou et al at OHSU analyzed 18 major studies involving over 85,000 people.

Compared to placebo, over 1-6 years statins reduced:

Heart attacks by 33%. 

Strokes by 22%

Risk of dying from any cause by  8%

The Bottom Line

Follow a diet rich in beans, lentils, nuts, fiber and unsaturated fats like olive oil. 

Keep blood sugar low and stable by eating protein at the beginning of each meal and do not skip meals.

Control blood pressure.

Avoid sitting for extended periods. Exercise regularly, especially resistance training.

Sleep adequately and treat sleep apnea or other sleep disorders.

Stop smoking and chewing tobacco.

Discuss blood tests and coronary calcium testing in the context of personal and family history.

Reduce stress.

Consider lipid lowering medications when indicated. 

In summary, the most effective prevention strategies lower cholesterol containing particles  while also improving the metabolic environment that makes arteries vulnerable to plaque formation.

 Select References:

1. Chou R, Cantor A, Dana T, et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2022.

2. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008.

3. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a Dietary Portfolio of Cholesterol-Lowering Foods vs Lovastatin on Serum Lipids and C-Reactive Protein. JAMA. 2003.

4. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia. J Am Coll Cardiol. 2026.

Consider forwarding this to a loved one-it may help someone you care about. Want to sign up for your own monthly Amuse-bouche op-ed series, in case this was forwarded to you? Go here. Want to check out prior editions of Amuse-bouche? Go here.

Medical disclaimer: These op-ed articles are for general informational purposes only and do not constitute the practice of medicine and no doctor/patient relationship is formed or implied. The use of information on this site or materials linked from this site is at the user’s own risk. The content of this article or site is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.

Proof of Life: Work along with Play

I grow Native plants (and some ornamentals like roses) because they thrive without too much watering and soil amendments, and support pollinators, but I didn’t realize that I was restricting water severely. With the heat wave, I decided to do some deep watering, and scores of flowers bloomed. Like rain in a desert. Duh!