Part I: Lipid and Lipoprotein Basics for Clinicians
What You Always Wanted to Know but Were Too Bored to Stay Focused On
It’s amazing how often I have conversations with patients and health care professionals who genuinely do not understand what they are asking or talking about when it comes to cholesterol, triglycerides, lipoproteins, and their treatment. That’s not because they are dumb or ignorant - they certainly are not. It’s because most people never have had the time, interest, or patience to learn what these words actually mean, why “LDL cholesterol” is not the same thing as “LDL,” what triglycerides really are, how lipid-lowering medications work, and what research really shows about the effects of diet on cholesterol and triglycerides.
So, drumroll … welcome to my Lipids and Lipoproteins Substack series, adapted from a set of lectures I give twice a year to medical students and cardiology fellows.
When people hear the words “lipids and lipoproteins,” their first reaction often is, “That sounds incredibly boring.” I get it. These topics are dense and very easy to teach badly. But I’ve always enjoyed teaching them and they consistently receive strong reviews, because once you understand a few core principles, treating lipid disorders stops being mysterious and starts to make sense. You start to recognize clinical patterns and treatment decisions feel logical rather than algorithmic. My challenge is translating live lectures, with diagrams, humor, and asides, into written form. I promise to do my best.
What This Series Is (and Is Not)
This series is an overview, not an exhaustive lipid textbook. Each section easily could be expanded into its own post and some will be. In particular, severe hypertriglyceridemia and HDL biology and clinical interpretation deserve their own focused discussion, as well as genetics and some emerging therapies.
My goal is to explain how I think about lipids clinically, using pathophysiology and guidelines as a foundation, by applying judgment where evidence, experience, and patient preferences warrant it. I will lay out the clinically relevant lipid and lipoprotein biology that explains how real patients with real diseases show up in clinic and how I make treatment decisions.
Today’s post is Part I: Lipid and Lipoprotein Basics for Clinicians. Next comes Part II: Causes and Treatments for Hypercholesterolemia - What You Really Need to Know, followed by Part III: Mixed Hyperlipidemia and Hypertriglyceridemia - Why “Normal LDL Cholesterol” Often Misses the Real Problem. Finally, Part IV: How I Treat Dyslipidemia in My Practice, which will put it all together. Each section is anchored by a real clinical case. HDL and severe hypertriglyceridemia are addressed only briefly here and intentionally saved for later.
Why Lipids Matter
Atherosclerosis is a response to arterial injury driven largely by inflammation and oxidative stress. Lipids matter because dyslipidemia is one of its major contributors. For more than 70 years, evidence from epidemiologic studies, human feeding studies, animal models, and large interventional trials has shown that cholesterol, particularly low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B–containing particles, predicts atherosclerosis, atherosclerotic vascular disease (ASCVD), and cardiovascular disease mortality.
Since average lipid levels in Western adults are roughly 30–50% higher than those seen in traditional hunter-gatherer societies, wild primates, or most mammals, and far higher than levels seen in umbilical venous blood from newborns, it should not be surprising that ASCVD is the leading cause of death and disability in the United States.
Case 1: A Young Man With Severe Hypercholesterolemia
Our first case is a 30-year-old man whose father had a heart attack at age 38. He is a non-smoker, physically active, and considers himself healthy. His wife is six months pregnant, so they undergo an insurance physical that reveals “high cholesterol.” He is six feet tall, weighs 180 pounds, and has a blood pressure of 118/74 mm Hg. His lipid panel shows a total cholesterol of 406 mg/dL, triglycerides 55 mg/dL, HDL cholesterol 50 mg/dL, and LDL cholesterol 345 mg/dL.
Before we discuss what to do, we need to ask some basic questions. What is LDL cholesterol? What even is cholesterol? And isn’t that really high? (yes, it is). Also, look at the knuckles and eyes in the representative images below – they are diagnostic for a disease:
What Are Lipids?
Lipids include cholesterol, triglycerides, and phospholipids. Cholesterol is a vital component of all cell membranes in the human body and a precursor for steroid sex hormones, vitamin D, and bile acids, reflecting its central role in human physiology. Because cholesterol is so essential, its levels are tightly regulated. In adults, this balance reflects roughly 800 mg per day of endogenous cholesterol synthesized in the liver and 200–300 mg per day of exogenously consumed cholesterol, primarily from animal products. These inputs are balanced by fecal loss of approximately 1,100 mg per day, largely as bile acids and unabsorbed cholesterol.
Triglycerides are long-chain fatty acids linked to a glycerol backbone. Saturated fatty acids contain no double bonds, monounsaturated fatty acids contain one, and polyunsaturated fatty acids contain more than one. Triglycerides are our primary form of fatty acid storage and play key roles in energy metabolism, thermoregulation, insulation, and organ protection.
Phospholipids are structural components of cell membranes and form amphipathic lipid bilayers. They consist of a hydrophilic head and hydrophobic fatty acid tails, forming external cellular barriers, intracellular membranes, and vesicles essential for cell structure, trafficking, and signal transduction.
What Are Lipoproteins?
The key reason we even are having these discussions is that cholesterol, triglycerides, and phospholipids are insoluble in plasma. Because plasma is mostly water and lipids don’t dissolve in it, they must be packaged into lipoprotein particles. Lipoproteins are spherical structures with a nonpolar core containing triglycerides and esterified cholesterol, surrounded by a polar surface composed of free cholesterol, phospholipids, and apolipoproteins. Without lipoproteins, lipids would separate from plasma like oil and water. Apolipoproteins are the key functional components. They confer solubility, regulate metabolism, and mediate interactions with enzymes and receptors. Clinically, lipoproteins matter because they mediate the major complications of dyslipidemia, most notably ASCVD.
We broadly classify lipoproteins into five major classes. Chylomicrons are large, triglyceride-rich particles synthesized in the intestine that carry dietary fat and are not atherogenic. They contain apolipoprotein B-48, marking their intestinal origin. Very low-density lipoproteins (VLDL) are synthesized in the liver, contain apolipoprotein B-100, and are atherogenic. Intermediate-density lipoproteins (IDL) are remnants of chylomicrons and VLDL and also are atherogenic. LDL is the dominant atherogenic particle, carries the most circulating cholesterol, and accounts for more than 90% of plasma apolipoprotein B-100. High-density lipoprotein (HDL) is a small, protein-rich particle involved in cholesterol trafficking and anti-inflammatory processes, but its clinical interpretation is more complex than once believed and will be addressed later. LDL particles are cholesterol-rich, contain apolipoprotein B-100, and are highly atherogenic. Approximately half of circulating LDL particles are cleared daily via hepatic LDL receptors. LDL receptor expression and cholesterol synthesis are tightly regulated by intracellular cholesterol content through HMG-CoA reductase activity (Sound familiar? - that is the enzyme inhibited by statins). When hepatic cholesterol levels are low, LDL receptors are upregulated, increasing LDL clearance from plasma. When hepatic cholesterol levels are high, receptor expression falls and LDL accumulates in circulation.
Distinguishing between lipids and lipoproteins is not just pedantic. It is critical to understand the difference between “LDL-C” – the cholesterol carried by LDL, and “LDL” – the particle that carries the cholesterol. It is essential for understanding the dyslipidemias we commonly see today and for predicting responses to therapy. I hope this chapter and the next one help make that clear.
What We Measure in the Clinic
When the lab report says “Total cholesterol” it’s a measurement of the cholesterol contained in all plasma lipoproteins. “HDL cholesterol” reflects cholesterol carried within HDL particles and serves as a surrogate for the HDL particle concentration. “Triglycerides” are a measure of the triglycerides in all lipoproteins. When people are fasting, the triglycerides are mostly in VLDL, but when non-fasting or in certain disorders, they can be in chylomicrons too.
“LDL cholesterol” represents the cholesterol inside of all of the LDL particles, but it’s an imperfect surrogate for the LDL particle concentration. It traditionally has been estimated using the Friedewald equation (LDL-C = total cholesterol minus HDL-C minus triglycerides/5), which becomes inaccurate at higher triglyceride levels and is invalid when triglycerides exceed 350–400 mg/dL. The NIH-Sampson LDL-C equation is much more accurate, especially when triglycerides are over 150 mg/dL, when LDL-C is <70 mg/dL, or in non-fasting samples, but still do not directly measure LDL particle burden.
Clinically Relevant Lipoprotein Metabolism
OK, wake up and strap yourself in for the hardest part. The enzymes and transporters matter clinically, because defects at any step can produce genetic dyslipidemia and nearly every step represents a potential therapeutic target.
Cholesterol homeostasis is tightly regulated with the liver serving as the central clearinghouse. Two interconnected pathways govern lipoprotein metabolism: (i) the exogenous pathway on the left of the image below, which addressed dietary cholesterol and cholesterol in the bile, and (ii) the endogenous pathway on the right of the picture below, which addresses cholesterol synthesis in the liver and other aspects of its metabolism.
In the exogenous pathway, dietary cholesterol mixes with biliary cholesterol in the intestinal lumen, is micellized, and transported into enterocytes via the NPC1L1 transporter. Of interest, that micellization process is blocked by plant stanols and sterols and the NPC19L1 transporter is blocked by the medication, ezetimibe, as we will discuss in the in the next blog. Cholesterol is esterified and packaged with triglycerides and apolipoprotein B-48 into chylomicrons. A significant fraction of intestinal cholesterol is pumped back into the lumen via ABCG5 and ABCG8 and ultimately excreted. FYI, if ABCG5/G8 are mutated, you will develop sitosterolemia! Bile acids are reabsorbed in the distal ileum and return to the liver via the portal circulation. That is why people without a terminal ileum get bile acid diarrhea and have low cholesterol levels. Did you know that a randomized clinical trial back in the 1970s-80s (the “POSCH” trial) evaluated partial ileal bypass surgery to lower cholesterol by enhancing bile acid loss? It reduced LDL cholesterol by 35-40%, reduced ASCVD events, and cardiovascular disease mortality (Buchwald H, et al. N Engl J Med 1990;323:946–955). That study validated LDL receptor upregulation as a therapeutic target, which is the basis of statin, ezetimibe, and other LDL-lowering therapies, as we will discuss in the next post. This also is why bile acid binding resins lower cholesterol, as discussed in Part II.
Chylomicrons enter the circulation through the lymphatic system, acquire apolipoprotein CII (which activates lipoprotein lipase [LPL]) and apolipoprotein E, and interact with LPL in muscle, heart, and adipose tissue. LPL hydrolyzes triglycerides, releasing free fatty acids for energy use or storage. The resulting chylomicron remnants are smaller, cholesterol-enriched particles that can be taken up by the liver via apo E or contribute to atherosclerosis.
In the endogenous pathway, the liver packages cholesterol and triglycerides with apolipoprotein B-100 into VLDL particles. VLDL also acquires apo CII and Apo E. As it circulates, LPL mediates triglyceride hydrolysis, leaving behind IDL particles. IDL can be cleared by the liver via apo E or further processed by hepatic lipase (HL), ultimately forming LDL. Once again, each of these lipoproteins and enzymes can be mutated and cause dyslipidemia; they can be harnessed as targets for drug therapy.
Thought Experiment Before Part II
That is enough physiology for today. You’ve made it through the hardest part. One final question to think about: What happens to LDL cholesterol if someone has defective LDL receptors or not enough of them?
We’ll answer that next Sunday in Part II: Hypercholesterolemia - Causes and Treatment, Explained. There we start reviewing the direct clinical application of the material above. It’s lighter from here on, I promise!
Note on references: This post reflects well-established lipid and lipoprotein biology. The concepts discussed are foundational and drawn from lectures I have delivered for the past 23 years. More details can be found in standard lipid textbooks and clinical guidelines; therefore, references are limited to image sources and a small number of illustrative primary citations.
I appreciate this review!
I’m curious to know your thoughts on the use of stenols/sterols as a nutritional supplement starting point in patients who have mild cholesterol elevation but are apprehensive about starting a statin. Alongside other lifestyle modifications, of course.
Some very important explanations in this post; for example:
“It is critical to understand the difference between “LDL-C” – the cholesterol carried by LDL, and “LDL” – the particle that carries the cholesterol.”