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All cells require lipids (fats) to synthesize membranes and provide energy. Lipids are transported in the blood as lipoproteins. These small particles consist of a core of triglycerides and cholesteryl esters, surrounded by a coat of phospholipids, cholesterol and proteins termed apolipoproteins or apoproteins. Apoproteins stabilize the lipoprotein particles and help target specific types of lipoproteins to various tissues. Hyperlipidaemias are abnormalities of lipoprotein levels which promote the development of atherosclerosis (see Chapter 37) and coronary heart disease (CHD; see Chapters 40–42).

Lipoproteins and lipid transport
Figure 36 illustrates pathways of lipid transport in the body. The exogenous pathway (left side of Figure 36) delivers ingested lipids to the body tissues and liver. Ingested triglycerides and cholesterol are transported by the protein Niemann–Pick C1-like 1 (NPC1L1) into the mucosal cells lining the intestinal lumen, which combine them with apoprotein apo B-48, forming nascent chylomicrons which are secreted into the lymph, pass into the bloodstream, and combine with apo E and apo C-II to become chylomicrons. These bind to the capillary endothelium in muscle and adipose tissue, where apo CII activates the endothelium-bound enzyme lipoprotein lipase (LPL)
which hydrolyses the triglycerides to fatty acids which enter the tissues. The liver takes up the residual chylomicron remnants. These are broken down to yield cholesterol, which the liver also synthesizes. The rate-limiting enzyme in hepatic cholesterol synthesis is hydroxy-methylglutaryl coenzyme A reductase (HMG-CoA reductase). The liver uses cholesterol to make bile acids. These pass into the intestine and act to solubilize dietary cholesterol so it can be absorbed via NPC1L1. Bile acids are almost entirely reabsorbed and returned to the liver, although about 0.5 g/day is lost in the faeces, providing a path by which the body excretes cholesterol.
The endogenous pathway cycles lipids between the liver and peripheral tissues. The liver forms and secretes nascent very low density lipoproteins (VLDLs), consisting mainly of triglycerides with some cholesterol and apo B-100, into the lacteal vessels. These acquire apo E and apo C-II from HDL in the plasma to become VLDL. As with chylomicrons, apo C-II activates LPL causing VLDL triglyceride hydrolysis and provision of fatty acids to body tissues. As it is progressively drained of triglycerides, VLDL becomes intermediate density lipoprotein (IDL) and then low-density lipoprotein (LDL), losing all of its apoproteins (to HDL) except for apo B-100 in the process. Most of the LDL, which contains mainly cholesteryl esters (CE), is taken up by the liver; the rest serves to distribute cholesterol to the peripheral tissues. Cells regulate their cholesterol uptake by expressing more LDL receptors (which bind to apo B-100) when their cholesterol requirement increases.
Cholesterol is removed from tissues by high-density lipoprotein (HDL). HDL is initially assembled in the plasma from lipids and apoproteins (mainly apo A1, but also apo C-II and apo E) lost by other lipoproteins, and then progressively accumulates cholesterol (which it stores as CE) from body tissues. Cholesteryl ester transfer protein (CETP), which is in the plasma, transfers these from HDL to VLDL, IDL and LDL, which return them to the liver. This process by which HDL transports cholesterol to the liver from the rest of the body is termed reverse cholesterol transport, and probably explains why plasma HDL levels are inversely proportional to the risk of developing CHD.

Hyperlipidaemias: types and treatments Primary hyperlipidaemias are caused by genetic abnormalities affecting apoproteins, apoprotein receptors or enzymes involved in lipoprotein metabolism, and occur in about 1 in 500 people. Secondary hyperlipidaemias are caused by conditions or drugs (e.g. diabetes, renal disease, alcohol abuse, thiazide diuretics) affecting lipoprotein metabolism. However, hypercholesterolaemia is most commonly caused by consumption of a diet high in saturated fats, probably because this decreases hepatic lipoprotein clearance. Although hyperlipidaemia often involves simply an excess of LDL cholesterol (LDL-C), many people, especially those with metabolic syndrome (see Chapter 34) have a combination of high LDL-C, high triglycerides (high VLDL), and low HDL cholesterol (HDL- C) levels in their plasma. This pattern is thought to confer a particularly large risk of developing CHD.
The treatment of hyperlipidaemias aims to slow or reverse the progression of atherosclerotic lesions by lowering LDL-C and/or triglycerides and to raise HDL-C. Current US guidelines state that LDL-C should be <160 mg/dL (4.1 mmol/L) for those who are otherwise at low risk of developing CHD, whereas for high-risk patients with existing CHD, diabetes or a 10-year risk of developing CHD of >20%, LDL-C should be <100 mg/dL (2.6 mmol/L), and ideally less than 70 mg/dL (1.8 mmol/L).
Treatment often begins with a low fat, high carbohydrate diet. If this fails to normalize hyperlipidaemia adequately after 3 months, therapy with a lipid-lowering drug is considered. The vast majority of those with high LDL-C receive ‘statins’, which have been consistently shown to reduce CHD and the mortality it causes. Those with high triglycerides and low HDL-C are also often given ‘fibrates’ or niacin (each used by 10% of patients).

HMG-CoA reductase inhibitors or ‘statins’ include simvastatin, lovastatin, pravastatin, fluvastatin, mevastatin, atorvastatin and rosuvastatin. The landmark Scandinavian Simvastatin Survival Study (4S) reported in 1994 that treatment with simvastatin of CHD patients with high LDL-C reduced cardiovascular mortality by 42% over a 6-year period. Statins act by reducing hepatic synthesis of cholesterol, causing an upregulation of hepatic receptors for B and E apoproteins. This increases the clearance of LDL, IDL and VLDL from the plasma. Statins also modestly increase plasma HDL-C levels by an unknown mechanism. Although the main benefits of statins result from their lipid-lowering effects, they also probably reduce CHD through additional mechanisms. These include an enhancement of nitric oxide release, possibly due to activation of the PI3K–Akt pathway (see Chapter 24), and also anti-inflammatory and antithrombotic effects. Some of these effects occur because the inhibition of HMG-CoA reduces cellular concentrations of lipids required for the functioning of the monomeric G proteins Rho (Rho acts to suppress eNOS expression) and Ras (Ras stimulates NFκB, which is involved in the expression of many pro-inflammatory genes). Serious statin-associated adverse effects are rare. They include hepatoxicity and rhabdomyolysis (destruction of skeletal muscle), the risk of which is increased with concomitant use of nicotinic acid or a fibric acid derivative.
Both niacin (nicotinic acid) and fibrates (fibric acid derivatives) are mainly used in patients who are receiving statins but whose triglyceride levels are too high (≥1.7 mmol/L or 150 mg/dL) and HDL-C levels are too low (<1.0 mmol/L or 40 mg/dL). Niacin is a B vitamin that has lipid-lowering effects at high doses. It inhibits the synthesis and release of VLDL by the liver. Because VLDL gives rise to IDL and LDL, plasma levels of these lipoproteins also fall. Conversely, HDL levels rise significantly as a result of decreased breakdown, an effect which the ARBITER 2 study (2004) showed may slow the progression of atherosclerotic plaque in patients with low HDL. Most patients experience flushing with niacin therapy. This is due to vasodilatation caused by prostaglandin release from the endothelium, and can be prevented by non- steroidal anti-inflammatory drugs. Other reported adverse effects include hepatotoxicity, palpitations, impaired glucose tolerance, hyperuricaemia, hypotension and amblyopia.
Fibrates include gemfibrozil, clofibrate, bezafibrate, ciprofibrate and fenofibrate. Fibrates bind to peroxisome proliferator-activated receptor alpha (PPARα) to stimulate the expression and activity of LPL, thereby reducing VLDL triglycerides by increasing their hydrolysis. They also promote changes in LDL composition, which render it less atherogenic, and enhance fibrolysis. They cause mild gastrointestinal disorders in 5–10% of patients, and can potentially cause muscle toxicity and renal failure if combined with HMG-CoA reductase inhibitors or excessive alcohol use.

Bile acid sequestrants: bile acids are synthesized from cholesterol in the liver, and cycle between the liver and intestine (enterohepatic recirculation). Cholestyramine and cholestipol are exchange resins that bind and trap bile acids in the intestine, increasing their excretion. This enhances hepatic bile acid synthesis and cholesterol utilization. The resulting depletion of hepatic cholesterol causes an upregulation of LDL receptors, increasing the clearance of LDL-C from the plasma. Bile acid sequestrants cause little systemic toxicity because they are not absorbed. However, they must be taken in large amounts (up to 30 g/day) and cause gastrointestinal side effects such as emesis, diarrhoea and reflux oesophagitis, so are rarely used.

Ezetimibe reduces absorption of dietary cholesterol by inhibiting the functioning of NPC1L1. This reduces the plasma concentration and hepatic uptake of chylomicrons. The liver responds to this by expressing more LDL receptors to maintain its cholesterol uptake, and plasma LDL-C levels fall by 15%. Ezetimibe, widely used together with statins, is a controversial drug, as the ENHANCE (2008) and ARBITER 6 (2009) studies showed that this combination was no better than a statin alone in reducing plaque progression, whereas a statin–niacin combination was.
Anacetrapib simultaneously lowers plasma LDL-C and strongly increases HDL-C by inhibiting CETP, and is currently in Phase 3 trials for treatment of atherosclerosis.