Modified forms of lipoproteins are associated with atherosclerotic pathophysiology, and oxidised low-density lipoprotein (LDL) particles are well known to be involved in the development of cardiovascular disease (CVD) [1]. Recently, oxidised forms of high-density lipoprotein (HDL) have also been recognised, and importantly, the particles are likely to impair the l atheroprotective functionality of HDL [2, 3]. Circulating levels of oxidised HDL (oxHDL) can be measured to see the presence of CVD [2].
γ-Glutamyl transferase (GGT) is a cell-surface enzyme that acts on the cleavage of glutathione, a major antioxidant [3]. GGT is not only a measure of liver diseases and alcoholism but also a marker of oxidative stress [3]. Oxidative stress induces GGT gene expression, and GGT also generates reactive oxygen species as a pro-oxidant molecule in association with traditional cardiometabolic risk factors [3]. Notably, an increase in GGT levels is a predictor of the development of CVD, even with relatively low GGT activity [3].
While the relationship of GGT with CVD is recognised, whether or not oxHDL is associated with GGT is unclear. The present pilot study investigated the correlation between GGT and oxHDL in healthy subjects with not-very-high GGT levels.
The present study included apparently healthy subjects (n = 19), with the following subjects excluded: those with a CVD history, any drug use, habitual drinking, any known liver diseases, plasma glucose ≥ 7.0 mmol/l, systolic/diagnostic blood pressure ≥ 140/90 mm Hg, and GGT < 70 IU/l [4, 5]. The Ethics Committee approved the study (No. 18-102), and all subjects gave their informed consent.
In fasted serum samples, biochemical variables (glucose, lipids, creatinine, alanine transaminase, and GGT) were measured using standard enzyme methods, while oxHDL was measured for plasma HDL using an enzyme-linked immunosorbent assay (OxiSelect Human Oxidized HDL (Malondialdehyde-HDL) Kit; Cell Biolabs, Inc., San Diego, CA, USA). The simple correlations between oxidised HDL and the other variables were examined by Pearson’s correlation test as well as a linear regression analysis adjusted for some variables. A p < 0.05 was considered significant.
Table I shows the clinical characteristics of the study subjects and the simple correlations between each characteristic variable and oxidised HDL. A significant positive correlation was observed between GGT and oxHDL. In linear regression analyses, their correlation remained significant (correlation adjusted for age and gender = 0.75, p < 0.01; adjusted for age, gender, and HDL-cholesterol = 0.88, p < 0.01).
Table I.
Clinical characteristics and simple correlations with oxidised HDL
| Variables | Characteristics | Correlations |
|---|---|---|
| Age [years] | 46.3 ±11.1 | 0.05 (0.85) |
| Men, n (%) | 13 (68) | 0.23 (0.35) |
| Smoker, n (%) | 2 (11) | –0.07 (0.76) |
| Body mass index [kg/m2] | 23.4 ±3.1 | 0.12 (0.63) |
| Systolic blood pressure [mm Hg] | 118 ±11 | 0.19 (0.44) |
| Diastolic blood pressure [mm Hg] | 72 ±10 | 0.11 (0.65) |
| Creatinine [µmol/l] | 60.9 ±10.8 | –0.10 (0.68) |
| Glucose [mmol/l] | 5.18 ±0.54 | 0.45 (0.06) |
| LDL-cholesterol [mmol/l] | 2.98 ±0.75 | 0.40 (0.09) |
| Triglyceride [mmol/l] | 0.80 (0.59–1.20) | 0.08 (0.73) |
| HDL-cholesterol [mmol/l] | 1.65 ±0.40 | 0.25 (0.31) |
| Alanine transaminase [U/l] | 17 (15–27) | 0.37 (0.12) |
| γ-glutamyl transferase [U/l] | 17 (15–25) | 0.64 (< 0.01*) |
| Oxidised HDL [ng/ml] | 1.5 (1.2–1.9) | – |
HDL – high-density lipoprotein, LDL – low-density lipoprotein. Characteristic data are shown as the mean ± standard deviation, median (interquartile range), or subject number (%). Simple correlations are shown as Pearson’s correlation coefficient (p-value) between each characteristic variable and oxidised HDL. Triglyceride, alanine transaminase, γ-glutamyl transferase, and oxidised HDL were calculated after a log-transformation because of their skewed distributions. Significance: *p < 0.05.
A positive relationship between GGT and oxHDL, independent of HDL-cholesterol, was thus detected in healthy subjects with not-very-high GGT levels. Although these data are preliminary, it is important to suggest that oxHDL may be partly linked to the relationship of GGT with CVD via HDL dysfunctionality (e.g. impairment of anti-inflammatory, anti-thrombotic, and antioxidative properties) [3].
The present study had several limitations. The study population was relatively small and limited to non-diseased individuals. The data were obtained only by a kind of oxHDL measurement. The cross-sectional study did not mention the precise causality; thus, how HDL is oxidised (e.g. the mechanism and organs involved) remains unclear. These points should be explored in further research.
Acknowledgments
This work was partly supported by a MEXT KAKENHI Grant (No. JP 19K07872).
Conflict of interest
The authors declare no conflict of interest.
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