Regulation of Plasma PAI-1 Concentrations in HAART-Associated Lipodystrophy During Rosiglitazone Therapy

Abstract

Objective-Patients with highly active antiretroviral therapy-associated lipodystrophy (HAARTϩLDϩ) have high plasminogen activator inhibitor-1 (PAI-1) concentrations for unknown reasons. We determined whether (1) plasma PAI-1 antigen concentrations are related to liver fat content (LFAT) independently of the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in these patients. Methods and Results-In the cross-sectional study, 3 groups were investigated: 30 HIV-positive patients with HAARTϩLDϩ, 13 HIV-positive patients without lipodystrophy (HAARTϩLDϪ), and 15 HIV-negative subjects (HIVϪ). In the treatment study, the HAARTϩLDϩ group received either rosiglitazone (8 mg, nϭ15) or placebo (nϭ15) for 24 weeks. Plasma PAI-1 was increased in HAARTϩLDϩ (28Ϯ2 ng/mL) compared with the HAARTϩLDϪ (18Ϯ3, PϽ0.02) and HIVϪ (10Ϯ3, PϽ0.001) groups. LFAT was higher in HAARTϩLDϩ (7.6Ϯ1.7%) than in the HAARTϩLDϪ (2.1Ϯ1.1%, PϽ0.001) and HIVϪ (3.6Ϯ1.2%, PϽ0.05) groups. Within the HAARTϩLDϩ group, plasma PAI-1 was correlated with LFAT (rϭ0.49, PϽ0.01) but not with subcutaneous or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose tissue, PAI-1 mRNA was 2-to 3-fold higher in the HAARTϩLDϩ group than in either the HAARTϩLDϪ or HIVϪ group. Rosiglitazone decreased LFAT, serum insulin, and plasma PAI-1 and increased serum triglycerides but had no effect on intra-abdominal or subcutaneous fat mass or PAI-1 mRNA. Conclusions-Plasma PAI-1 concentrations are increased in direct proportion to LFAT in HAARTϩLDϩ patients.Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data suggest that liver fat contributes to plasma PAI-1 concentrations in these patients.

Increased resting energy expenditure, fat oxidation, and food intake in patients with highly active antiretroviral therapy-associated lipodystrophy

“…As previously described (29,(51)(52)(53)(54)61), the age, body mass index, and total body fat mass values were comparable between the HAARTϩLDϩ and the HAARTϩLDϪ groups. The HAARTϩLDϩ group had, however, significantly less subcutaneous fat (1,100 Ϯ 200 vs. 1,800 Ϯ 300 cm 3 , P Ͻ 0.05) and more intra-abdominal fat (1,900 Ϯ 200 vs. 900 Ϯ 300 cm 3 , P Ͻ 0.01) than the HAARTϩLDϪ group ( Table 1).…”

“…As previously described, the patients were recruited from the outpatient clinic of the Helsinki University Central Hospital (29,(51)(52)(53)(54)61). All participants had to have been treated with combination antiretroviral therapy for at least 18 mo before enrollment and did not have any signs or symptoms of current opportunistic infections.…”

Genes Involved in Fatty Acid Partitioning and Binding, Lipolysis, Monocyte/Macrophage Recruitment, and Inflammation Are Overexpressed in the Human Fatty Liver of Insulin-Resistant Subjects

“…The fatty liver of obese mice overexpresses plasminogen activator inhibitor 1 (PAI-1) (9). We have previously demonstrated circulating PAI-1 concentrations to be closely correlated with liver fat content in patients with lipoatrophy (10), but it is unknown whether the human fatty liver of insulin-resistant subjects overexpresses MCP-1, macrophage inflammatory protein (MIP)-1␣, CD68, or PAI-1.…”

Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity

“…Insulin resistance in the liver results in VLDL overproduction, which leads to hypertriglyceridemia and low HDL cholesterol levels (2). The liver, once fatty, also overproduces fibrinogen, von Willebrand factor, C-reactive protein (3), and plasminogen activator inhibitor (PAI)-1 (3,4). Resistance to insulin inhibition of hepatic glucose production basally and postprandially results in hyperglycemia and hyperinsulinemia (1).…”