Fast Facts: Hyperlipidemia: Bringing clarity to lipid management

Introduction

Why is there a need for a sixth edition of Fast Facts: Hyperlipidemia? The answer is that, first, there have been great advances in our understanding of hyperlipidemia and many more are waiting in the wings. Information about new drugs, a wider knowledge of how to use earlier ones and avoid side effects, improved means of diagnosis, the expanding role of genetics and much more are covered in this book. We have attempted to introduce these in a way that we hope will appeal to clinicians who wish to brush up on the subject and to those who may be coming to it with little prior knowledge (or interest, which we hope the book will arouse).

Second, probably more importantly, many aspects of hyperlipidemia continue to spark controversy in medical journals that frequently spills over into the lay press and social media. Much of the controversy is fueled by official guidance which, instead of digesting our accumulated knowledge and translating it objectively into practical information, adopts a peculiar logic leading to treatment paradigms that are bizarre and unfamiliar to doctors and nurses and their patients. ‘The best lack all conviction, while the worst are full of passionate intensity.’* The ensuing confusion has undoubtedly led to the inefficient deployment of statins and a failure to secure their full benefit in the prevention of atherosclerotic cardiovascular disease. This must be resolved and mistakes not repeated as our knowledge and the range of available treatments enter a new era.

A clear and logical approach to hyperlipidemia is thus our main justification for this new edition.

*From ‘The Second Coming’, WB Yeats.

1Lipids and lipoprotein particles

Cholesterol and triglycerides are not soluble in water and must be transported from one tissue to another within lipoprotein particles.¹–⁴ Chylomicron particles transport triglycerides from the intestines to adipose tissue, skeletal and cardiac muscle and the liver, and cholesterol from the intestines to the liver. Very-low-density lipoprotein (VLDL) particles transport triglycerides from the liver to adipose tissue and skeletal and cardiac muscle. High-density lipoprotein (HDL) particles transport cholesterol from peripheral tissues to the liver.

The structure of a lipoprotein particle is illustrated in Figure 1.1. A phospholipid monolayer makes up the outer membrane and cholesteryl ester and triglycerides make up the core. Apolipoproteins are the protein components; these differ in function and ability to leave one lipoprotein particle for another.

Lipoprotein particles

There are four key types of lipoprotein particle: chylomicrons and VLDL are the two triglyceride-rich lipoproteins, whereas low-density lipoprotein (LDL) and HDL are the two cholesterol-rich lipoproteins (Figure 1.2).

Lipid and lipoprotein metabolism

Biological role of triglycerides and fatty acids. Triglyceride is a major source of energy that is stored in adipose tissue both subcutaneously and internally. Subcutaneously, adipose tissue insulates against heat loss, whereas internally, it protects the internal organs against physical damage. Triglycerides can be transported in lipoproteins, while the constituent fatty acids – termed non-esterified fatty acids (NEFA) – can be transported after hydrolysis by a lipase (lipolysis). NEFA circulate bound to albumin.

Figure 1.1 The structure of a lipoprotein particle. The most hydrophobic components (the triglycerides and cholesteryl esters) form a central droplet, which is surrounded by the more polar components (free cholesterol, proteins and phospholipids). Proteins are arranged with their hydrophobic sequences inside the particle and their hydrophilic regions oriented toward the aqueous environment (outside). The polar groups of cholesterol and phospholipids also point outward, away from the hydrophobic core. LCAT, lecithin–cholesterol acyltransferase.

Triglyceride transport and storage. Triglycerides are an almost ideal form of energy storage and consequently are, far and away, the major form in which we store energy. Almost one-fifth of the total mass of a lean 70-kg adult man is made up of triglyceride in adipose tissue. If oxidized, this would yield 570 000 kilojoules – roughly enough energy to survive total starvation for 3 months.

Figure 1.2 The four types of lipoprotein particle: chylomicrons, VLDL, LDL and HDL. Apo, apolipoprotein; CE, cholesteryl ester; Tg, triglyceride.

Adipose tissue is the major site of triglyceride storage. Morphologically, an adipose cell appears to be no more than a rim of cytoplasm around a large droplet of triglyceride. These cells, however, are much more metabolically active than their structure suggests. Not only is the rate at which they take up and release fatty acids tightly regulated, but they also synthesize and secrete a wide variety of bioactive molecules.

Visceral adipose tissue produces inflammatory cytokines, like tumor necrosis factor (TNF) and interleukin 6 (IL-6), which cause insulin resistance. Consequently, NEFA release from adipose tissue, which would otherwise be suppressed by insulin, is increased. When there is central obesity, these processes are important in the genesis of metabolic syndrome and type 2 diabetes (see Chapter 7).

Chylomicron, VLDL and LDL metabolism is illustrated in Figure 1.3. Dietary triglycerides undergo digestion to fatty acids and monoglycerides in the gut. These are absorbed into the enterocytes, resynthesized into triglycerides and packaged into chylomicrons, and then enter the circulation for transport to the tissues. Fat absorption is generally complete within a few hours; during this time, plasma triglyceride levels increase, though the degree to which they do so is very modest in healthy people. In some people, however, triglyceride clearance is delayed and substantial postprandial hypertriglyceridemia results.

At the capillary endothelial surfaces in adipose tissue and cardiac and skeletal muscle, the enzyme lipoprotein lipase (LPL) rapidly breaks down the triglycerides within chylomicrons, releasing fatty acids. LPL is activated by insulin and apolipoprotein C-II (ApoC-II) and inhibited by apolipoprotein C-III (ApoC-III). Both chylomicrons and VLDL (see later) acquire these C apolipoproteins in the circulation. Peroxisome proliferator-activated receptors (PPARs), particularly PPARα, increase the clearance of both chylomicrons and VLDL by inducing LPL synthesis and by inhibiting ApoC-III production. This is part of the mechanism by which fibrate drugs, which are PPAR agonists, lower plasma triglycerides.⁵ The fatty acids released by LPL are taken up by myocytes and adipocytes, where they can be oxidized immediately for energy or resynthesized into triglycerides and stored. Fatty acids that are released but not taken up locally are bound to albumin and circulate as NEFA in plasma. Adipose tissue can also store triglyceride that it synthesizes from glucose.

Chylomicron remnants. After encountering LPL, chylomicrons become chylomicron remnants, relatively triglyceride poor and cholesterol rich. Normally, these remnants are rapidly removed by the liver via receptor-mediated mechanisms that involve a multifunctional receptor, the LDL receptor-related protein (LRP), which is assisted by the proteoglycan heparan sulfate on the surface of hepatocytes and by the LDL receptor. The chylomicron remnant ligand for these receptors is apolipoprotein E (ApoE), which chylomicrons acquire during their time in the circulation (see Chapter 6). In contrast to intact chylomicrons, which are too large to enter the arterial wall, the smaller chylomicron remnants can do so and are proatherogenic.

Figure 1.3 Metabolism of chylomicrons, VLDL and LDL. Triglyceride (Tg) is released from chylomicrons and VLDL as glycerol, monoglycerides and NEFA. Apo, apolipoprotein; IDL, intermediate-density lipoprotein; LRP, LDL receptor-related protein.

VLDL is the triglyceride-rich lipoprotein secreted continuously by the liver. In healthy individuals, VLDL makes the largest contribution to serum triglycerides. Its rate of secretion is determined by the flux of NEFA to the liver from adipose tissue and by hepatic fatty acid synthesis from glucose. When fatty acids entering the liver from NEFA are not converted to ketones, as they would be in starvation, they are esterified to glycerol to form triglycerides and secreted within VLDL particles. If the hepatic capacity to secrete triglycerides within VLDL particles is exceeded, fatty liver (hepatic steatosis) can occur. n-3 fatty acids reduce hepatic triglyceride synthesis by decreasing the flux of NEFA to the liver from adipose tissue.⁶

VLDL particles undergo the same metabolic fate as chylomicrons, with one important difference. Just as with chylomicrons, the triglyceride within VLDL particles is broken down by LPL on the capillary endothelium of muscle and adipose tissue, and fatty acids are released that may be taken up by adipose tissue or muscle or circulate as NEFA. However, whereas the chylomicron remnants produced are, in general, rapidly removed from the circulation by the liver, most VLDL particles become converted to LDL particles (see Figure 1.3).

LDL particles persist in plasma nine times longer than VLDL particles. That is why there are, in general, nine times more LDL than VLDL particles. In addition, LDL particles are much smaller than VLDL particles and can pass through the vascular endothelium much more easily. Those two facts explain why LDL is more directly important in atherogenesis than VLDL.

Starvation. The adipose triglyceride store is our main source of energy when food is in short supply. As insulin levels fall in starvation, fatty acids are mobilized from the triglyceride stored in adipose tissue by activation of intracellular hormone-sensitive lipase. The liver partially oxidizes these fatty acids to ketone bodies, which it releases into the circulation. Ketone bodies are small water-soluble molecules that can readily enter the Krebs (tricarboxylic acid) cycle and replace glucose as a source of energy in all tissues apart from the brain. For the brain, with its absolute requirement for glucose as 40% of its energy source, glycogen as a source of glucose is expended after a day or so. Because fatty acids cannot be converted to glucose, glucose must then come from breakdown of protein, leading to muscle wasting.

Diabetes and insulin resistance. In type 1 diabetes mellitus, inadequate insulin means that the mechanisms that exist to combat an energy-deficient diet come into play maladaptively, with excessive release of NEFA, ketogenesis and muscle breakdown leading to diabetic ketoacidosis. At the other end of the spectrum, food excess leads to obesity due to increased adipose tissue deposits. Abdominal adiposity (android pattern) is particularly associated with a combination of hyperinsulinemia and insulin resistance and phenomena such as hypertriglyceridemia, low HDL and, as we shall see in Chapter 4, increased numbers of small dense LDL particles.

Biological role of cholesterol

Cholesterol is an essential component of all cell membranes, where it occupies spaces between the molecules of the phospholipid bilayer, reducing its fluidity. Cholesterol is the precursor for bile acid, steroid hormone and vitamin D synthesis.

Cholesterol metabolism and transport in lipoproteins. Typically, the daily cholesterol intake is 200–500 mg/day, whereas the total dietary fat intake is 80–100 g/day. Furthermore, cholesterol absorption from the gut is incomplete, with only 30–60% of dietary cholesterol actually entering the body. Chylomicrons transport the cholesterol of exogenous origin from the intestine to the liver, where the chylomicron remnants are taken up (see Figure 1.3).

In total, the body synthesizes at least as much cholesterol as it absorbs. Although all cells in the body can synthesize cholesterol, most cholesterol synthesis is centralized in the liver, gut and central nervous system (CNS). Most cells are in contact with LDL as it is small enough to cross the vascular endothelium of all tissues other than the CNS (blood–brain barrier); they can synthesize LDL receptors, which bind to apolipoprotein B100 (ApoB100), permitting LDL entry into the cell to supply cholesterol.

Cholesterol biosynthesis is extremely complex. However, a key regulatory step occurs early in the pathway, at the point where 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) is converted to mevalonic acid. The enzyme responsible, HMG-CoA reductase, can be inhibited by a variety of factors, the most important of which for clinical purposes are the statin drugs (otherwise known as HMG-CoA reductase inhibitors). Recently, it has been discovered that ATP citrate lyase (ACLY) – important for the hepatic conversion of citrate to acetyl coenzyme A (acetyl-CoA), a precursor of both HMG-CoA and fatty acid synthesis – can influence cholesterol biosynthesis. Bempedoic acid inhibits ACLY, lowering serum LDL-cholesterol.⁷

The liver is the central clearing house for cholesterol, with several ways in and out. When cytoplasmic cholesterol levels decline in the liver, hepatic LDL receptor expression increases. Examples of when this may occur include:

•with statin treatment

•when cholesterol reabsorption from the small intestine is decreased by cholesterol absorption inhibitors, such as plant sterol or stanol esters added to food products ⁸ or the drug ezetimibe ⁹

•when no cholesterol is entering the body from the diet.

Both ApoB100 and ApoE are ligands for LDL receptors and are critical for the removal of both LDL and chylomicron remnants from the circulation. Clearance of LDL by the LDL receptor via ApoB100 is impaired in familial hypercholesterolemia (FH). Most commonly, this is due to mutation of the receptor itself. Genetic variants of ApoB100 also occur that have lower binding affinity, and gain-of-function mutations affecting PCSK9, which encodes proprotein convertase subtilisin/kexin type 9 (PCSK9), can promote the intracellular degradation of LDL receptor, thus interrupting recycling of the receptor between endosomes and the cell surface (see Chapter 3). Inhibition of PCSK9 provides a means of increasing LDL receptor recycling to the hepatocellular surface and thus enhancing LDL removal from the circulation.¹⁰

Apolipoprotein B48 (ApoB48) does not possess the LDL receptor-binding domain present in ApoB100, making receptor binding