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HDL or not HDL, that is the question

‘HDL or not HDL, that is the question’ that literaryminded diabetic patients may perhaps be tempted to ask. High density lipoprotein (HDL), for which the cholesterol component usually serves as a marker, is a powerful, negative coronary risk factor [1]. Raised serum concentrations of HDL are consistently associated with reduced incidence of coronary disease. However, type 1 diabetic patients are at increased risk of coronary disease [2], despite HDL levels significantly higher than in nondiabetic subjects. The study by Mackness et al. [3] in this issue may provide one explanation for this apparently paradoxical situation. They report that serum levels of the HDL-associated antioxidant enzyme, paraoxonase-1 (PON1), are significantly lower in type 1 diabetic patients, despite higher concentrations of serum HDL. It confirms an earlier report by Boemi et al. [4] and consolidates accumulating evidence that diabetic patients, both type 1 and 2, are deficient in PON1 [4,5]. Although not addressed in the present study, the shortfall in PON1 (of a similar magnitude to that observed by Boemi et al. [4]) was sufficient to influence the antioxidant capacity of HDL in vitro in the preceding report [4]. The latter is an important point, as the antioxidant function of HDLassociated PON1, notably its ability to protect LDL from oxidation, has been clearly linked to atherosclerosis in animal models. In PON1 knockout mice, absence of PON1 increased atheroma formation and lipoprotein oxidation. The modulated, protective action of HDL was not reflected in HDL levels that were unaltered [6]. Data from human patients have also revealed a less efficient PON1 antioxidant function in coronary patients in whom HDL levels did not differ from controls [7]. These studies, together with other data, provide firm evidence for a role of PON1 in the atherosclerotic process. The mechanism probably involves the antioxidant capacity of the enzyme, which was first hypothesised by the Mackness group [8]. Given the prominent role attributed to lipoprotein oxidation in atherosclerosis [9], one possible extrapolation of the data from the two studies is that a reduced antioxidant capacity may be a contributory factor to increased risk of coronary disease in type 1 diabetic patients. In this respect, a recent study is intriguing as it concluded that at equivalent concentrations, diabetic LDL was more atherogenic (toxic) than nondiabetic LDL [10]. Could it reflect a greater degree of lipoprotein oxidation? Also to be considered is the observation that in serum, the majority of oxidised lipids appears to circulate in HDL [11]. PON1 protects both HDL as well as LDL lipids from oxidation [12]; reduced PON1 together with increased serum HDL (as frequently observed in type 1 diabetic patients) translates into a lower PON1 : lipid ratio within HDL. Is this desirable in a group subject to greater oxidative stress? The answer would appear to be ‘no’ as there is evidence that oxidised HDL would appear to function less efficiently in the reverse cholesterol transport pathway where it has a reduced capacity to promote efflux of cholesterol from cells [12,13]. Such observations should provide the stimulus for further studies of the pathological consequences of reduced HDL-PON1. These are necessary if we are to consider the observations in diabetic patients to be of clinical relevance. The wider implications of the observations are that the protective influence of HDL may be compromised in certain groups of patients and this may not be adequately reflected by routine measures used to quantify serum HDL. It prompts reflection on the extent to which the antiatherogenic influence of HDL is the sum of its component parts. Evidence exists for a beneficial, modulatory role of HDL in diverse processes impacting on atherosclerosis (antioxidant, anti-inflammatory, anti-cytolytic, antiapoptotic, reverse cholesterol transport, catabolism of triglyceride-rich lipoproteins). The protective role required of HDL may thus depend on which processes are defective in different individuals. In this respect, diabetes is considered to promote oxidative stress [14], in part due to the raised serum glucose concentrations [15,16]. Consequently, a deficiency in PON1 may be more deleterious in this group of patients. The present study serves to underline Correspondence to: Richard W. James, Clinical Diabetes Unit, Division of Endocrinology and Diabetes, Faculty of Medicine, University Hospital, 1211 Geneva 14, Switzerland. Tel.: + 41–22–3729304; Fax: + 41–22–3729309; e-mail: Richard.James@hcuge.ch