Effects of cigarette smoking on HDL quantity and function: Implications for atherosclerosis.

He BM, Zhao SP, Peng ZY
J Cell Biochem. 2013 Jul 15. doi: 10.1002/jcb.24581

Background

It has long been established that cigarette smoking is an independent risk factor for atherosclerosis and coronary heart disease. The underlying mechanisms are however unclear, although evidence points in the direction of endothelial dysfunction, platelet activation, increasing oxidative stress and inflammation. Cigarette smoking also appears to disrupt lipid and lipoprotein metabolism; smokers have elevated plasma cholesterol, triglycerides and LDL-c, and lower HDL-c levels as compared to non-smokers. In particular the effects of cigarette smoking on HDL appears to contribute to the increased risk of CV disease in smokers. This review will outline these effects in more detail.

Cigarette smoking associated with low HDL-c levels

Several studies have shown that male and female smokers have significantly lower HDL-c levels than non-smokers. Also passive cigarette smoking has a negative effect on the level of HDL-c. This effect of cigarette smoking is dose-dependent. In contrast, smoking cessation can elevate HDL-c, up to levels seen in non-smokers.

Effects of cigarette smoking on HDL metabolism
HDL metabolism is a complex process consisting of biosynthesis and maturation step, and intravascular remodelling and HDL catabolism. Many enzymes and transfer proteins are involved, and can thus be modified by cigarette smoking.

Effects of cigarette smoking on HDL biosynthesis and maturation
HDL biosynthesis involves the synthesis and secretion of lipid-poor apolipoprotein A-I (apoA-1) followed by acquisition of cholesterol and phospholipids from the liver, forming nascent HDL particles. Cigarette smoking can decrease the level of apoA-I. ApoA-I deficiency results in impaired HDL synthesis. Cessation of smoking restored apoA-I concentration.
Nascent HDL particles acquire additional free cholesterol from extrahepatic tissues. This cholesterol is then esterified to cholesteryl ester by lecithin cholesterol acyltransferase (LCAT). This enzyme is crucial for the maintenance of normal HDL metabolism, and rapid catabolism of apoA-I and –II. Lower plasma LCAT concentrations and activity have been measures in smokers. Also in an experimental setting, cigarette smoke directly diminished plasma LCAT activity. Maturation of HDL may be affected by reduced LCAT activity, thereby inducing rapid clearance of nascent HDL from the circulation.

Effects of cigarette smoking on intravascular remodelling of HDL
The rate of HDL clearance from the circulation is greatly affected by intravascular remodelling of HDL particles, which includes lipid exchange and lipolytic modification. Lipolytic enzymes and lipid transfer factors such as cholesterol ester transfer protein (CETP) facilitate the exchange of cholesteryl ester in HDL for triglycerides in LDL and VLDL. CETP enhances the triglyceride content in HDL, and decreases HDL-c levels. Some studies have shown elevated CETP activity in smokers, while another reported that smoking did not affect CETP activity.
Hepatic lipase can catalyze hydrolysis of HDL triglycerides and phospholipids, and its concentration is therefore inversely related to HDL-c levels. Increased hepatic lipase activity has been measured in smokers. Another study however reported tat normolipidemic smokers had 30% lower hepatic lipase activity, as compared to nonsmokers.

Effects of cigarette smoking on HDL subfractions
LCAT, CETP and hepatic lipase metabolise HDL in the arterial wall and in plasma. LCAT generates large HDL2, and CETP redistributes and remodels HDL into small HDL3 particles, which are subsequently hydrolysed by lipase.
Smoking may affect these different HDL subfractions. The HDL2 subfraction appears to be reduced by smoking, while HDL3 does not seem to be affected. Second-hand smoke also seems to lower HDL2.

Effects of cigarette smoking on HDL catabolism
HDL transports excess cholesterol from peripheral cells to the liver and steroidogenic cells for catabolism, thereby regulating cholesterol balance. The liver is the main site of HDL-c uptake. Cigarette smoking can impair hepatic uptake of HDL-c, at least in pigeons.

Effects of cigarette smoking on HDL function

Evidence is accumulating that HDL does not always have atheroprotective properties, that it may be dysfunctional under certain circumstances.

Impaired HDL atheroprotective properties by oxidative modifications
Several oxidants can modify HDL, including cigarette smoking. Formation of lipid peroxidation derivatives can change HDL conformation and physiological properties. This may lead to loss of the atheroprotective properties. Oxidised HDL has been detected in the intima of atheromatous plaques, which increased the severity of disease. Oxidised HDL may further impede the reverse cholesterol transport, enhance oxidation of LDL and increase vascular inflammation.

Effects of cigarette smoking on lipid peroxidation
Oxidants in tobacco smoke can furthermore induce oxidative stress. Gas phase radicals in cigarette smoke can modify macromolecules, including lipids. LDL isolated from smokers was found to be more susceptible to oxidation than LDL from nonsmokers. Indeed, levels of oxidized LDL were higher in smokers.

Effects of cigarette smoking on oxidative modification of HDL
HDL peroxidation was increased upon exposure to cigarette smoke. The apolipoprotein composition of HDL is also susceptible to oxidative modification by cigarette smoking. HDL can be oxidatively modified by cigarette smoking not only by production of reactive oxygen radicals but also by weakening of the antioxidant enzymes in HDL.

Effects of cigarette smoking on dysfunction of HDL
Cholesterol efflux activity of HDL was reduced upon experimental exposure to cigarette smoking. This effect was found to be mediated by lipid peroxidation.

Conclusion

The negative impact of cigarette smoking on risk of cardiovascular disease seem to be mediated through its effects on lipid and lipoprotein metabolism. Cigarette smoking in particular affects HDL, Lowering its concentration and modification of HDL might make it lose its protective properties or even become atherogenic.

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