In Part 1 of this series, we looked at the history of heart disease and how it rose from a rare and mysterious affliction at the start of the 20th century to the world’s number one killer by the end of it. We looked at competing theories as to its cause, especially sugar vs. saturated fat. Ancel Keys’ “lipid hypothesis” remains prominent today, pointing to saturated fat in the diet raising cholesterol levels in the blood, which causes atherosclerotic plaques to accumulate in the arteries of the heart. But is it true that cholesterol is enemy No. 1 in the battle against heart disease? To explore this question, we must first understand cholesterol itself.
Cholesterol 101
Cholesterol is a waxy, fat-like molecule that is essential to life. It is a type of lipid, but not a fat in the way we typically think of dietary fat. Cholesterol plays a structural role in every cell membrane in the body, helping to regulate fluidity and integrity. Notably, the brain is ~25% cholesterol, and this crucial substance is required to make new brain cells and new neuronal connections. It is also a precursor to several operational systems of the body, including steroid hormones (cortisol, estrogen, and testosterone), vitamin D, and bile acids that help us digest fat. Without cholesterol, our cells would collapse like popped balloons, hormones would vanish, fat would become indigestible, and life as we know it would cease in a biochemical freefall. It’s that important.
Roughly 80% of the cholesterol in your body is made endogenously, primarily by the liver, through a multi-step biochemical pathway (we’ll return to this in the next installment on statins). Only about 20% comes from dietary sources. This internal production is tightly regulated by the body to ensure that adequate cholesterol is available for critical functions. How much cholesterol you consume directly from foods like egg yolks, shrimp, and fish roe has basically no effect on total cholesterol in the blood. If dietary intake of cholesterol decreases, the body compensates by producing more. If intake increases, the body tends to produce less. This built-in feedback loop reflects how essential cholesterol is to survival and cellular function.
The Lipoprotein Carriers
Despite its importance, cholesterol cannot dissolve in water or blood on its own. To travel through the water-based highway of the bloodstream, it must be packaged into specialized transport vehicles called lipoproteins. These lipoproteins are spherical particles made of fats and proteins (hence lipo + protein), which carry cholesterol (along with other cargo like triglycerides and phospholipids) to and from tissues. The most commonly discussed types are low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Less talked about are chylomicrons, Very Low Density Lipoproteins (VLDL), and Intermediate-Density Lipoproteins (IDL). It is essential to distinguish that LDL and HDL are not types of cholesterol; they are carriers of cholesterol. Lipoproteins are like boats or taxis, which may differ in structure and function, but the passengers (cholesterol) are all the same.
The confusion between cholesterol itself and the lipoproteins that carry it has led to widespread misunderstanding. There is no “good cholesterol” and “bad cholesterol.” To be told you have “high cholesterol” — primarily when referring to high TC (aka, Total Cholesterol) — is essentially meaningless. What matters when it comes to predicting future health outcomes is much more nuanced. How many and what types of particles are in circulation? How long have they been in circulation? Have they become oxidized? What health/metabolic states are causing these numbers to be high or low?
Other measurements like LDL particle count (LDL-P), NMR Profile (size and count of particles), Oxidized LDL (oxLDL), and ApoB (apolipoprotein B) offer more meaningful insights. ApoB is a protein found on the surface of each particle (including LDL, VLDL, and IDL), so the total ApoB count reflects the number of particles in circulation.
People with insulin resistance tend to have small, dense LDL particles, which are more likely to penetrate the arterial wall and become oxidized, initiating plaque formation. In contrast, large, buoyant LDL particles are less atherogenic. This is why two people with the same LDL-C can have very different cardiovascular risk profiles.
The Misunderstood Marker
For decades, LDL-C has been the primary focus of cholesterol testing and treatment. But its predictive power is limited. Many people who suffer heart attacks have “normal” LDL-C levels, and many people with elevated LDL-C never experience cardiovascular disease.
One large-scale analysis found that 75% of patients who presented to the hospital for a heart attack had LDL-C levels indicating they were not at high risk for a cardiovascular event, and 50% had levels considered “optimal” (below 100mg/dL or 2.6 mmol/L).
LDL does more than just transport cholesterol. It also plays a vital role in the body’s innate immune system. LDL particles can bind and neutralize bacterial endotoxins such as lipopolysaccharides (LPS), helping to reduce systemic inflammation and infection risk. They act as molecular scavengers, mopping up harmful substances in the bloodstream and delivering them to the liver for disposal. In this way, LDL serves a dual purpose: delivering essential cholesterol to cells while also participating in immune defense, particularly in the early stages of microbial exposure. Low LDL may also leave the immune system weakened and less able to fight early tumor progression in the development of cancer. Research indicates a robust association of low LDL and cancer development, but it is unclear whether low LDL causes cancer or is related in some other way.
Low LDL is consistently shown to be associated with higher mortality, especially in older adults. In simple terms, those with the lowest LDL cholesterol are the most likely to die in the follow-up period (here, here, and here, for example). Perhaps this is because older adults are at higher risk of both cancer and septic infections? Again, the causation (if any) is not clear.
Another wildly interesting observation? Those with low cholesterol levels are also much more likely to commit violent crimes in the future, and low cholesterol is strongly associated with attempted suicide, particularly via violent methods. Since cholesterol is such an integral part of the brain, it is hypothesized that low cholesterol impairs the brain’s ability to engage in executive functions such as mood regulation and impulse control.
The Numbers that Matter
A more nuanced approach to predicting CVD risk considers whether LDL-C levels are discordant with other markers. For example, someone with high LDL-C but low triglycerides and high HDL may be at low risk of CVD, especially if they are metabolically healthy. In the medical literature, this is known as a Lean Mass Hyper-responder phenotype. Conversely, someone with normal LDL-C but high triglycerides and low HDL may be at much greater risk.
One of the most powerful, inexpensive, and underutilized markers for cardiovascular risk is the triglyceride-to-HDL ratio. Research has shown this ratio to be a strong predictor of insulin resistance, metabolic syndrome, and future cardiovascular events. It outperforms LDL-C in predicting risk, particularly in people with normal or borderline LDL levels. The TG:HDL ratio correlates closely with the presence of small, dense LDL particles and other atherogenic changes that accompany poor metabolic health. This simple calculation reflects the state of metabolic health and insulin sensitivity:
- A low TG:HDL ratio (<1.5 in mg/dL or <0.87 in mmol/L) suggests good insulin sensitivity.
- A high TG:HDL ratio indicates insulin resistance, poor lipid handling, and higher cardiovascular risk.
In short, LDL-C in isolation is a poor marker for heart disease risk and even worse for overall mortality. Looking at the complete metabolic picture provides more accurate and actionable information. Why is there an obsessive focus on lowering LDL-C in the healthcare industry then? Well, unlike LDL-C, there are currently no effective drugs to raise HDL or lower triglycerides in a meaningful way. With nothing to sell to treat those numbers, they get largely ignored. Follow the money, as they say.
In the next article, we’ll explore statins: the most widely prescribed class of cholesterol-lowering drugs. We’ll look at what they actually do, who they help, and what risks they carry.
About the Author
Jocelyn Rylee (CF-L4) and her husband David founded CrossFit BRIO in 2008, starting in a modest 1500 sq ft space and focusing on personal training. Her dedication to excellence has also earned her a position on CrossFit LLC’s Level 1 Seminar Staff, a role that allows her to share her passion and expertise with aspiring coaches. Jocelyn holds specialties in Endurance, Gymnastics, Competition, and Weightlifting and is also a certified Strength and Conditioning Specialist through the NSCA. As a Level 2 Olympic Weightlifting Coach and a Level 3 referee, she has been deeply involved in the sport, even serving as a board member of the Saskatchewan Weightlifting Association for five years. Her achievements include being Saskatchewan’s top-ranked female Olympic Weightlifter from 2012 to 2015, during which she held provincial records in the Snatch, Clean & Jerk, and Total in her weight class. With an MS in Human Nutrition, Jocelyn loves sharing her knowledge on nutrition and performance through her blog and Instagram as “The Keto Athlete,” where she delves into the science of nutrition and its impact on athletic performance.