Potential Mechanisms for the Smoking-Related Reduction in HDL-C

Because of the intrinsic link between plasma TAG and HDL metabolism, demonstrated by their negative association in populations, and the biological effects of smoking on plasma TAG metabolism (Freeman and Packard 1995), it is likely that changes in plasma HDL-C concentration could be an indirect effect of smoking-related increases in plasma TAG concentration. Indeed, much of the effect of smoking on plasma HDL is lost after statistical correction for changes in plasma TAGs (Freeman et al. 1993; Phillips et al. 1981). Cigarette smoking affects the activities of plasma enzymes involved in regulating HDL size and turnover: lecithin–cholesterol acyltransferase (LCAT) (Freeman et al. 1998; Haffner et al. 1985) and lipoprotein lipase (LPL) (Freeman et al. 1998; Elkeles et al. 1983) activities are reduced, whilst HL (Moriguchi et al. 1991) and CETP (Dullaart et al. 1994) activities are increased. These changes result in a shift in the size distribution of HDL into smaller particles which have increased clearance from the plasma compartment (Brinton et al. 1994). However, there is a residual effect of smoking after correction for changes in plasma TAG, suggesting TAG-independent effects of smoking on plasma HDL concentration also exist. These TAG-independent effects appear to be more important in men than women (Freeman et al. 1993).

There is evidence for structural/compositional changes in HDL brought about by smoking. Ex vivo experiments, in which human plasma was acutely exposed to cigarette smoke, resulted in cross-linking of apoA-I and apoA-II (McCall et al. 1994) that may impair activation of LCAT. Similarly, chemically crosslinked HDL has an increased clearance in rodents (Senault et al. 1990). Smoking is associated with a reduction in the HDL content of Lp-PLA2, an enzyme thought to play an anti-atherogenic role in HDL (Tselepis et al. 2009). Early studies showed that chronic inhalation of cigarette smoke in pigeons inhibits liver HDL uptake (Mulligan et al. 1983). Recent data have shown that a by-product of cigarette smoking, benzo(a)pyrene, inhibited apoA-I synthesis in HepG2 cells, via activation of the aryl hydrocarbon nuclear steroid receptor, whilst nicotine had no effect (Naem et al. 2012). Modelling of the monocyte transcriptome in smokers compared to non-smokers identified SLC39A8 to be on a causal pathway between smoking and plaque formation (Verdugo et al. 2013). This gene is known to be associated with the cellular uptake of cadmium from tobacco and was negatively associated with HDL cholesterol levels in this study.

There are very few studies on the effects of smoking on HDL function. HDL isolated from smokers showed reduced ability to induce cholesterol efflux from macrophages, possibly via apoA-I-mediated effects (Kralova Lesna et al. 2012). Ex vivo cigarette smoke treated HDL, which resulted in an increased conjugated diene and denatured apoA-I content, reduced the efflux capacity of HDL to a level similar to that of copper-oxidised HDL (Ueyama et al. 1998). Co-incubation with superoxide dismutase prevented approximately half of the impairment and reduced the level of conjugated dienes, but not the apoA-I denaturation. There is also some evidence that plasma thiocyanates found in high levels in smokers could cause HDL oxidation and reduced apoA-I cholesterol efflux ability (Hadfield et al. 2013). Smoking is associated with reduced activity and concentration of PON1, an HDL-associated antioxidant enzyme, effects which are reversed after smoking cessation (James et al. 2000). The mechanistic data for the effects of smoking on HDL function are far from comprehensive and merit further investigation.