No abstract

Infection causes disturbances in lipid metabolism that may be mediated by cytokines. Therefore we studied plasma lipids, lipoproteins, triglyceride (TG) metabolism, and serum cytokines in three groups: patients with the acquired immunodeficiency syndrome (AIDS) without active secondary infection, patients with evidence of human immunodeficiency virus infection but without clinical AIDS (HIV+), and controls. Plasma TGs and FFA were increased in AIDS, while plasma cholesterol, high density lipoprotein (HDL) cholesterol, apolipoprotein-A-1 (Apo-A-1), low density lipoprotein (LDL) cholesterol, and Apo-B-100 levels were decreased. Increased TG levels in AIDS were primarily due to increases in very low density lipoprotein of normal composition; in addition, LDL and HDL were TG enriched. In HIV+, TGs and FFA were not increased, but total cholesterol, HDL cholesterol, Apo-A-1, and Apo-B-100 were significantly decreased. Interferon-alpha (IFN alpha) and C-reactive protein levels were increased in AIDS, but tumor necrosis factor and haptoglobin levels were not. There was a significant correlation between plasma TGs and IFN alpha levels (r = 0.477; P less than 0.01), but not between TGs and tumor necrosis factor, C-reactive protein, haptoglobin, or P-24 antigen. In addition, there was no relationship between circulating IFN alpha levels and plasma cholesterol, HDL cholesterol, Apo-A-1, LDL cholesterol, Apo-B-100, or FFA. TG clearance time and postheparin lipase were significantly decreased in AIDS and HIV+. There was a strong correlation between serum IFN alpha levels and TG clearance time in AIDS and HIV+ (r = 0.783; P less than 0.001). In summary, decreases in cholesterol and cholesterol containing lipoproteins (including HDL) in both AIDS and HIV+ precede the appearance of hypertriglyceridemia and are not related to IFN alpha or TG levels. Our data raise the possibility that with development of AIDS, subsequent increases in IFN alpha may contribute to increases in plasma TG levels in part by decreasing the clearance of TG.

The acute phase response (APR) is associated with decreased hepatic expression of many proteins involved in lipid metabolism. The nuclear hormone receptors peroxisome proliferator-activated receptor ␣ (PPAR␣) and liver X receptor (LXR) play key roles in regulation of hepatic lipid metabolism. Because heterodimerization with RXR is crucial for their action, we hypothesized that a decrease in RXR may be one mechanism to coordinately down-regulate gene expression during APR. We demonstrate that lipopolysaccharide (LPS) induces a rapid, dose-dependent decrease in RXR␣, RXR␤, and RXR␥ proteins in hamster liver. Maximum inhibition was observed at 4 h for RXR␣ (62%) and RXR␤ (50%) and at 2 h for RXR␥ (61%). These decreases were associated with a marked reduction in RXR␣, RXR␤, and RXR␥ mRNA levels. Increased RNA degradation is likely responsible for the repression of RXR, because LPS did not decrease RXR␤ and RXR␥ transcription and only marginally inhibited (38%) RXR␣ transcription. RXR repression was associated with decreased LXR␣ and PPAR␣ mRNA levels and reduced RXR⅐RXR, RXR⅐PPAR and RXR⅐LXR binding activities in nuclear extracts. Furthermore, LPS markedly decreased both basal and Wy-14,643-induced expression of acyl-CoA synthetase, a well characterized PPAR␣ target. The reduction in hepatic RXR levels alone or in association with other nuclear hormone receptors could be a mechanism for coordinately inhibiting the expression of multiple genes during the APR.Small lipophilic compounds, such as steroids, thyroid hormones, vitamin D, and retinoids, regulate gene expression by binding to nuclear hormone receptors (1-3). Nuclear hormone receptors are the largest known family of transcription factors, with over 150 members currently. The nuclear hormone receptors share a common structural composition, including a central, highly conserved DNA-binding domain and a carboxylterminal domain that mediates ligand recognition, receptor dimerization, and ligand-dependent activation (1-3).The nuclear receptor superfamily has been divided into four major subgroups according to their dimerization and DNA binding properties (3). Class II receptors consist of nuclear receptors that heterodimerize with the retinoid X receptor (RXR) 1 and usually bind to direct repeats separated by a variable number of spacer nucleotides (3, 4). The class II subgroup includes the retinoic acid receptor (RAR), thyroid hormone receptor, vitamin D receptor, farnesoid X receptor, peroxisome proliferator-activated receptor (PPAR), and liver X receptor (LXR) (3, 5). Three distinct RXR genes have been cloned: RXR␣, RXR␤, and RXR␥.