Zinc Alpha-2 Glycoprotein and Dyslipidaemia in HIV Patients
Zinc Alpha-2 Glycoprotein and Dyslipidaemia in HIV Patients
In this study, we found that circulating ZAG protein levels were lower in HIV-1-infected patients who were receiving cART than in healthy uninfected subjects. Also, in infected patients, plasma ZAG levels were directly determined by HDLc levels, suggesting a role in lipid metabolism in these patients. This effect was unrelated to the presence of lipodystrophy.
ZAG is a protein that is widely distributed among several body fluids, including blood. Recently, adipose tissue has been revealed to be an important target for this protein, with a possible role in lipolytic activity in this tissue. Furthermore, the ZAG protein may also be synthesized and secreted by mature adipocytes, with a close regulatory link with some adipokines and transcription factors such as peroxisome proliferator activated receptor gamma (PPARγ). Increased lipolysis may be a deleterious effect of many antiretroviral drugs from various drug families. In our study, no relationship was found between ZAG levels and the family of antiretroviral drugs used. However, we cannot discount the possibility of a global effect on ZAG plasma levels in the HIV-1-infected group as a consequence of cART, because no data for naïve HIV-1-infected patients were available. Nevertheless, the absence of differences in ZAG level between lipodystrophy and nonlipodystrophy patients suggests an effect linked to HIV-1 infection itself rather than a metabolic effect. Notably, in contrast to the findings of previous studies in a healthy population, in which ZAG was found to be lower in patients with obesity, no differences in ZAG level were observed in the subpopulation of HIV-infected patients with a worse metabolic profile (the lipodystrophy subset) or when patients were stratified according to the components of MS. In all, these data indicate a possible effect of HIV-1 infection on ZAG synthesis and secretion. Longitudinal studies in HIV-1-infected patients before and after starting cART could help to ascertain the differential effects of the drugs and of HIV-1 itself.
Inflammatory responses observed in treated HIV-1-infected patients may result from a combined effect of antiretroviral drugs, increased lipolytic activity and metabolic disturbances that occur in these patients. ZAG activity has been inversely linked to pro-inflammatory cytokines, and, in our cohort, a negative correlation was initially observed with sTNFR2 and IL-6, which are cytokines with a well-recognized pro-inflammatory effect. Interestingly, lipodystrophy and nonlipodystrophy subjects did not show any differences in these inflammatory parameters. This may partly explain the absence of differences in ZAG levels, despite a worse metabolic profile, in the lipodystrophy group compared with those without lipodystrophy. In contrast, this subgroup of patients presented low adiponectin circulating levels, a high HOMA index and low HDLc levels, all of which have been associated, in previous reports, with lower ZAG plasma levels. We have no satisfactory explanation for these discrepancies but we are aware that the study design does not allow us to draw valid conclusions in this regard.
One of the main functions of ZAG is linked to lipid homeostasis. Experimental data indicate that this protein stimulates glycerol release and induces lipolytic activity in adipose tissue. Administration of ZAG in ob/ob mice induces a reduction in fat mass with an increase in adipose tissue expression of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). This is paralleled by a reduction in TG plasma levels with an increase in glucose transporter (GLUT4) in both skeletal muscle and adipose tissue. Consistent with these findings in mice, the main determinant of ZAG circulating level in the HIV-1-infected cohort was HDLc plasma level (especially in men, because in women the median HDLc value was higher), independent of the inflammatory or insulin-resistance state. Recently, a metabolic link between the lipolytic activity of adipocytes and the rate of cellular cholesterol efflux to HDL has been described in mice adipocytes. Thus, the strong observed association between ZAG and HDLc plasma levels may reflect the lipolytic activity of ZAG in adipose tissue in HIV-1-infected patients.
Our study has some limitations. First, the cross-sectional nature of our design provides associations and not causality. Secondly, we defined lipodystrophy clinically. Because of the lack of objective measurements of body composition, we cannot discount the possibility that some patients in the nonlipodystrophy subset could have had some minor subclinical changes that were not clinically detectable. However, we believe that this is unlikely because the study cohort consisted of patients with extreme phenotypes. Thirdly, the uninfected control group consisted of hospital personnel. This may have introduced bias in several ways, such as biases related to diet and lifestyle, which may have affected the internal validity of the study. An additional bias in our data may have been introduced by the fact that controls were older and had a higher BMI than HIV-1-infected patients. Both age and BMI have been shown to influence ZAG level, although data are inconsistent. Finally, we acknowledge that the results provided here are preliminary and that further studies are needed to replicate our data.
In conclusion, HIV-1-infected patients were found to have lower plasma ZAG levels than UCs. These changes were mainly dependent on HDLc, but were also associated with total cholesterol, inflammatory markers and insulin.
Discussion
In this study, we found that circulating ZAG protein levels were lower in HIV-1-infected patients who were receiving cART than in healthy uninfected subjects. Also, in infected patients, plasma ZAG levels were directly determined by HDLc levels, suggesting a role in lipid metabolism in these patients. This effect was unrelated to the presence of lipodystrophy.
ZAG is a protein that is widely distributed among several body fluids, including blood. Recently, adipose tissue has been revealed to be an important target for this protein, with a possible role in lipolytic activity in this tissue. Furthermore, the ZAG protein may also be synthesized and secreted by mature adipocytes, with a close regulatory link with some adipokines and transcription factors such as peroxisome proliferator activated receptor gamma (PPARγ). Increased lipolysis may be a deleterious effect of many antiretroviral drugs from various drug families. In our study, no relationship was found between ZAG levels and the family of antiretroviral drugs used. However, we cannot discount the possibility of a global effect on ZAG plasma levels in the HIV-1-infected group as a consequence of cART, because no data for naïve HIV-1-infected patients were available. Nevertheless, the absence of differences in ZAG level between lipodystrophy and nonlipodystrophy patients suggests an effect linked to HIV-1 infection itself rather than a metabolic effect. Notably, in contrast to the findings of previous studies in a healthy population, in which ZAG was found to be lower in patients with obesity, no differences in ZAG level were observed in the subpopulation of HIV-infected patients with a worse metabolic profile (the lipodystrophy subset) or when patients were stratified according to the components of MS. In all, these data indicate a possible effect of HIV-1 infection on ZAG synthesis and secretion. Longitudinal studies in HIV-1-infected patients before and after starting cART could help to ascertain the differential effects of the drugs and of HIV-1 itself.
Inflammatory responses observed in treated HIV-1-infected patients may result from a combined effect of antiretroviral drugs, increased lipolytic activity and metabolic disturbances that occur in these patients. ZAG activity has been inversely linked to pro-inflammatory cytokines, and, in our cohort, a negative correlation was initially observed with sTNFR2 and IL-6, which are cytokines with a well-recognized pro-inflammatory effect. Interestingly, lipodystrophy and nonlipodystrophy subjects did not show any differences in these inflammatory parameters. This may partly explain the absence of differences in ZAG levels, despite a worse metabolic profile, in the lipodystrophy group compared with those without lipodystrophy. In contrast, this subgroup of patients presented low adiponectin circulating levels, a high HOMA index and low HDLc levels, all of which have been associated, in previous reports, with lower ZAG plasma levels. We have no satisfactory explanation for these discrepancies but we are aware that the study design does not allow us to draw valid conclusions in this regard.
One of the main functions of ZAG is linked to lipid homeostasis. Experimental data indicate that this protein stimulates glycerol release and induces lipolytic activity in adipose tissue. Administration of ZAG in ob/ob mice induces a reduction in fat mass with an increase in adipose tissue expression of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). This is paralleled by a reduction in TG plasma levels with an increase in glucose transporter (GLUT4) in both skeletal muscle and adipose tissue. Consistent with these findings in mice, the main determinant of ZAG circulating level in the HIV-1-infected cohort was HDLc plasma level (especially in men, because in women the median HDLc value was higher), independent of the inflammatory or insulin-resistance state. Recently, a metabolic link between the lipolytic activity of adipocytes and the rate of cellular cholesterol efflux to HDL has been described in mice adipocytes. Thus, the strong observed association between ZAG and HDLc plasma levels may reflect the lipolytic activity of ZAG in adipose tissue in HIV-1-infected patients.
Our study has some limitations. First, the cross-sectional nature of our design provides associations and not causality. Secondly, we defined lipodystrophy clinically. Because of the lack of objective measurements of body composition, we cannot discount the possibility that some patients in the nonlipodystrophy subset could have had some minor subclinical changes that were not clinically detectable. However, we believe that this is unlikely because the study cohort consisted of patients with extreme phenotypes. Thirdly, the uninfected control group consisted of hospital personnel. This may have introduced bias in several ways, such as biases related to diet and lifestyle, which may have affected the internal validity of the study. An additional bias in our data may have been introduced by the fact that controls were older and had a higher BMI than HIV-1-infected patients. Both age and BMI have been shown to influence ZAG level, although data are inconsistent. Finally, we acknowledge that the results provided here are preliminary and that further studies are needed to replicate our data.
In conclusion, HIV-1-infected patients were found to have lower plasma ZAG levels than UCs. These changes were mainly dependent on HDLc, but were also associated with total cholesterol, inflammatory markers and insulin.