HIV infection significantly reduces lipoprotein lipase which remains low after 6 months of antiretroviral therapy

Purpose of the study Fractional clearance rate of apolipoprotein B100-containing lipoproteins is reduced in HIV infection before and after antiretroviral (ARV) treatment [1]. We compared lipoprotein lipase (LPL) activity and gene expression in HIV-positive subjects before and 6 months after ARV with HIV-negative controls. Methods Fasting blood post heparin total and hepatic lipase activity,adiponectin, leptin, insulin, glucose, and lipid measurementswere made in 32 HIV-infected and 15 HIVnegative controls. LPL was estimated by subtractinghepatic lipase from total lipase. Adiponectin, LPL andhormone sensitive lipase (HSL) gene expression weremeasured from iliac crest subcutaneous fat biopsies.Patients were tested before, and 6 months after randomisation to AZT/3TC (n = 15) or TDF/FTC (n = 17) with EFV.Between-group comparison was by Mann-Whitney andpaired samples by the Wilcoxon signed rank tests. Summary of results There were no differences in gender, ethnicity, baseline BMI, regional fat distribution (whole body DEXA) and visceral (VAT) and subcutaneous fat (SAT) measured by abdominal CT scans between controls and patients. Trunk fat/BMI ratio, VAT and VAT:SAT ratio significantly increased after 6-month ARV therapy (p = 0.01). There were no differences between groups in serum NEFA,HOMA and leptin levels. Selected other results are shown in Table 1. Conclusion Post heparin lipoprotein lipase activity is reduced in HIV and does not return to control levels after 6 months of ARV therapy. AZT-containing regimens are associated with a greater increase in LPL, LPL gene expression and plasma adiponectin than TDF

The role of visfatin in adipose tissue metabolism and metabolic disease

It is clear that sub-clinical inflammation is a key factor that triggers type 2 diabetes mellitus (T2DM) and is directly influenced by weight gain. Current studies highlight that obesity, particularly central obesity, heightens the pathogenesis of T2DM. Additionally, factors produced by adipose tissue (AT), referred to as adipocytokines, can influence the degree of insulin resistance as well as inflammation, due to their duality of function. A recently implicated adipocytokine, visfatin, has been identified as a potential insulin mimetic, an enzyme associated with mitochondrial biogenesis and an inflammatory factor. However, current studies lack a clear understanding as to the role and influence of visfatin in human AT and insulin resistant states. Therefore, this thesis examined visfatin expression within specific human AT depots and the influence of adiposity - with specific consideration given to insulin resistant states including T2DM, non-alcoholic fatty liver disease (NAFLD) and human immunodeficiency virus (HIV). Further, serum studies addressed how different insulin resistant states influenced circulating visfatin levels, whilst mechanistic studies explored how the role of visfatin was altered by insulin, an insulin sensitiser, inflammation and/or disease. This current thesis identified that visfatin was abundant in both abdominal depots, with highest expression in the omental (Om) AT, and isolated adipocytes, with an apparent relationship with insulin resistance. Subsequent in vivo and in vitro analysis further identified that, whilst insulin appeared to increase visfatin protein expression in isolated abdominal subcutaneous (Abd Sc) adipocytes, the use of an insulin sensitiser - either used in cultured Abd Sc adipocytes or as part of an oral therapeutic treatment in subjects with T2DM - decreased circulating visfatin levels. In addition, intracellular signalling studies highlighted that visfatin regulation within AT appeared to be dependent upon both nuclear factor (NF)-B and c-Jun N-terminal kinase (JNK) activation, influencing interleukin (IL)-6 as part of a visfatin regulatory feedback mechanism. Following the potential influence of visfatin in T2DM, this thesis explored its’ potential role in disease associated with other insulin resistant phenotypes, such as liver disease and HIV. From serum assessment of visfatin in subjects with NAFLD, it was identified that progression of liver disease was accompanied by a reduction in circulating visfatin levels – a finding that occurred independently of diabetic status. However, circulating visfatin still remained significantly higher in NAFLD with T2DM than those without. Finally, this thesis examined a potentially severe insulin resistant phenotype noted in HIV patients, due to an apparent lipodystrophy - a condition which alters fat oxidation and mitochondrial activation or regulation. In such a condition, circulating visfatin levels and visfatin mRNA AT expression remained unaltered by HIV status or drug therapy. Due to the capacity of visfatin to act as an enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis, essential for mitochondrial function and oxidative phosphorylation (OXPHOS), its role in AT remained unchanged by disease status, whilst other mitochondrial and fat metabolism factors were altered by both disease state and drug treatment. Taken together, these current data suggest a duality of function of which visfatin appears to be regulated by insulin, in addition to inflammation, in different disease states and therefore expands our current understanding of this multi-functional adipocytokine

Adipocyte differentiation, mitochondrial gene expression and fat distribution : differences between zidovudine and tenofovir after 6 months

Background: Abnormal lipid metabolism and cell oxidative mechanisms are reported in patients on antiretroviral treatment. We compared the expression of several key adipocyte genes in HIV-infected patients randomized to antiretroviral regimens containing zidovudine (AZT) or tenofovir disoproxil fumarate (TDF). Methods: Subcutaneous fat was sampled from 32 HIV-positive treatment-naive patients before and 6 months after randomization to AZT/lamivudine/efavirenz (n=15) or TDF/emtricitabine/efavirenz (n=17) plus 15 HIV-negative matched controls. Expression of genes involved in adipocyte differentiation, lipid metabolism, mitochondrial function and glucocorticoid generation were profiled using real-time PCR. Lipoprotein lipase and hepatic lipase activity were assessed. Results: Before treatment, 11 beta-hydroxysteroid dehydrogenase expression was down-regulated compared with controls. Following 6 months treatment with AZT, there was a significant increase in visceral adipose tissue (VAT; P=0.02) and the ratio of VAT to subcutaneous adipose tissue (P=0.008), down-regulation of cytochrome B (P=0.003) and cytochrome oxidase (COX)-3 gene expression (P=0.03), up-regulation of NADH dehydrogenase (P=0.008) and nuclear-encoded COX-4 (complex IV) gene expression (P=0.012). Genes involved with adipocyte cortisol generation, fatty acid metabolism and the tricarboxylic acid cycle were up-regulated. In the TDF-treated patients, there was no significant change in regional body fat or mitochondrial genes compared with pretreatment values. Changes in the expression of genes involved with cortisol and fatty acid metabolism were less marked with TDF. Conclusions: Interference with the mitochondrial electron transport chain appears to occur early in an AZT-containing regimen and occurs at a time when there is increased visceral fat and up-regulation of genes involved with adipocyte differentiation and fatty acid flux