Finally, no significant correlations were
found between plasma ZAG and the remaining adipokines assessed. In this study, we found that circulating ZAG protein levels were lower in HIV-1-infected patients who were receiving Selleckchem Cabozantinib 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 [24]. 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) [9, 10, 25-27]. Increased lipolysis may be a deleterious effect of many antiretroviral drugs from various drug families [28, 29]. 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 GSK-3 inhibitor 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 [9, 11], 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 MTMR9 disturbances that occur in these patients [30]. 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.