Findings from the present study corroborate growing evidence suggesting that high selenium exposure is associated with increased serum lipid levels. In the present study, high serum selenium concentrations were associated with higher serum lipids in a representative survey of US adults ≥ 40 years old conducted in 2003–2004. The associations of selenium with total and LDL cholesterol levels were strong and linear. HDL cholesterol levels were also positively associated with selenium concentrations but only at the low end of the selenium distribution (up to the 20th percentile). The triglyceride-selenium relationship was U-shaped. These findings raise additional concerns about potential cardio-metabolic abnormalities associated with high-normal selenium status.
In agreement with the present study, an earlier cross-sectional analysis of serum selenium and blood lipids in the NHANES III (1988–1994), high serum selenium concentrations were associated with high total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, apolipoprotein B, and apolipoprotein A1 levels 9
. In the EVA (Epidemiology of Vascular Ageing) study, conducted in France, plasma selenium was positively associated with total cholesterol and LDL-cholesterol among men, and with HDL-cholesterol and apolipoprotein A-1 among women 12
. Furthermore, high-normal selenium status was associated with increased total and non-HDL cholesterol, but not with increased HDL, in the 2000–2001 UK National Diet and Nutrition Survey (NDNS), a nationally representative sample of British adults13
. Interestingly, British and French adults have substantially lower mean serum selenium levels compared to US adults. Positive associations of selenium status with total cholesterol levels have also been found in other populations with optimal or suboptimal selenium status, but those studies did not provide detailed dose-response analyses 14–16
. Altogether, the current epidemiological evidence consistently indicates that serum/plasma selenium is associated with blood lipids across a wide range of selenium concentrations.
Randomized evidence on the effect of selenium supplementation on lipid metabolism is limited. In a French population, the SU.MI.VAX (Supplementation with Antioxidant Vitamins and Minerals) trial showed that long-term daily supplementation with selenium (100 µg), vitamin C (120 mg), vitamin E (30 mg) and zinc (20 mg) resulted in higher serum triglyceride levels and higher total cholesterol levels among women, and higher use of lipid lowering medication among men 17
. In a randomized trial in a rural Chinese population with low selenium intake, long-term supplementation with selenium (37.5 µg), vitamin C (250 mg) and vitamin E (100 IU) resulted in small but significant increases in total and LDL cholesterol levels, whereas HDL concentrations were not affected 18
. These studies were multi-element supplementation trials and could not isolate the effect of selenium from that of other antioxidants administered. Two smaller, short-term intervention studies have examined the lipid profile effects of selenium supplementation alone, but their results were inconsistent 19 20
Current evidence on potential mechanisms for the effect of high selenium exposure on lipid metabolism is sparse and any such discussion is highly speculative. There is, however, evidence of a connection between lipoprotein and selenium metabolism. Small amounts of serum selenium can be identified in human lipoproteins 21
. Early studies found that an intravenously administered selenium isotope was mainly attached to very low density lipoproteins and low density lipoproteins 22
. Additionally, research on animal models suggests interdependence between selenoprotein and lipoprotein metabolic pathways. For example, selenoprotein P is taken up by the brain and the testes via
the apolipoprotein E receptor-2 23
, whereas megalin, another apolipoprotein receptor, mediates its uptake by the kidney 24
. In mouse knock-out models with impaired selenoprotein synthesis, liver apolipoprotein E concentrations, plasma cholesterol levels and the expression of genes involved in cholesterol biosynthesis, metabolism and transport are altered 25
. A further connection between selenium and cholesterol is found in the common use of isopentenyl pyrophosphate as a substrate for the synthesis of Sec-tRNA and of isoprenoid in the mevalonate pathway 26
. The formation of selenoproteins requires the isopentenylation of Sec-tRNA with isopentenyl pyrophosphate, a substrate that is also required by farnesyl pyrophosphate synthetase in the pathway to cholesterol. Finally, recent findings from the EVA study indicate that long-term use of fibrates (but not statins) may increase plasma selenium concentrations in dyslipidemic aged patients 27
, further supporting a link between selenium and lipid metabolism.
Notwithstanding the potential biological mechanisms involved, selenium is known to have a narrow therapeutic window and large inter-individual variability in the low adverse effect level (LOAEL) of dietary selenium 28
. Above the physiological range for optimal activity of antioxidant selenoproteins such as glutathione peroxidases (55 µg/day, resulting in serum or plasma concentrations of 70–90 µg/L) 29
, further increases in selenium intake result in the non-specific incorporation of selenomethionine replacing methionine in albumin and other proteins. The metabolic pathways involving this extra pool of selenium are incompletely understood, and may be responsible for some of the associations between selenium and lipids.
The present study is limited by its cross-sectional design, and we were unable to determine whether lipid levels rise as a consequence of increased selenium intake or whether a common metabolic pathway or common co-exposures might explain the association between selenium status and lipid levels. Besides, selenium data were only available for subjects above 40 years of age and the observed association could be different among younger individuals. The strengths of our study are the US population representativeness of the sample and the rigorous data collection and laboratory assays. The possibility of confounding by concomitant intake of high fat and high selenium foods was addressed through adjusting for cholesterol, total fat, saturated fatty acids, and selenium intakes, although measurement error in dietary data may result in residual confounding.
In addition to association with adverse lipid metabolism, high selenium exposure has been associated with other cardio-metabolic outcomes such as type 2 diabetes and hypertension 3–5 7
. Given high selenium intake from natural sources in the US and the increasing use of selenium enriched foods, supplements and fertilizers in many countries 30
, these findings call for a thorough evaluation of the risks and benefits associated with high selenium status. Indeed, in the present study mean serum selenium concentrations were 136.7 µg/L, substantially higher than mean concentrations in NHANES III (125.7 µg/L). The use of vitamin/mineral supplements has likely contributed to the increase in selenium levels over the last decade, as reflected by the high percentage of dietary supplement users in the top quartiles of serum selenium in the present study. Increasing selenium intake in individuals with a replete selenprotein status, such as the average NHANES participant, has little potential for additional health benefits but can result in toxic effects. The relationship between selenium status and atherosclerosis is more complex than its role as antioxidant and should be clarified to enlighten preventive and therapeutic uses of selenium and to help determine the optimal level of selenium intake in the general population that maximizes the antioxidant benefits but avoids potential subclinical toxic effects of selenium.