Publications

BACKGROUND

HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional adipose tissue depots and lipid levels is not defined.

METHODS

The association of magnetic resonance imaging-measured visceral adipose tissue (VAT) and regional subcutaneous adipose tissue (SAT) volume with fasting lipid parameters was analyzed by multivariable linear regression in 737 HIV-infected and 145 control men from the study of Fat Redistribution and Metabolic Change in HIV Infection.

RESULTS

HIV-infected men had higher median triglycerides (170 mg/dL vs. 107 mg/dL; P < 0.0001), lower high-density lipoprotein cholesterol (HDL-C; 38 mg/dL vs. 46 mg/dL; P < 0.0001), and lower low-density lipoprotein cholesterol (LDL-C; 105 mg/dL vs. 125 mg/dL; P < 0.0001) than controls. After adjustment, greater VAT was associated with higher triglycerides and lower HDL-C in HIV-infected and control men, whereas greater leg SAT was associated with lower triglycerides in HIV-infected men with a similar trend in controls. More upper trunk SAT was associated with higher LDL-C and lower HDL-C in controls, whereas more lower trunk SAT was associated with higher triglycerides in controls. After adjustment, HIV infection remained strongly associated (P < 0.0001) with higher triglycerides (+76%, 95% confidence interval [CI]: 53 to 103), lower LDL-C (-19%, 95% CI: -25 to -12), and lower HDL-C (-18%, 95% CI: -22 to -12).

CONCLUSIONS

HIV-infected men are more likely than controls to have higher triglycerides and lower HDL-C, which promote atherosclerosis, but also lower LDL-C. Less leg SAT and more VAT are important factors associated with high triglycerides and low HDL-C in HIV-infected men. The reduced leg SAT in HIV-infected men with lipoatrophy places them at increased risk for proatherogenic dyslipidemia.

OBJECTIVES

To assess long-term changes in subcutaneous tissue among antiretroviral-naive persons initiating 1 of 3 nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens.

METHODS

We compared changes in 308 participants initiating stavudine plus lamivudine (d4T+3TC; N = 63), zidovudine plus lamivudine (ZDV+3TC; N = 192), and abacavir plus lamivudine (ABC+3TC; N = 53), along with protease inhibitors and/or non-NRTIs. Anthropometric measurements (skinfolds) were performed at baseline and 4-month intervals. Rates of change (mm/y) over 36 months, for the early period (months 4 through 12) and late period (months 16 through 36), were calculated.

RESULTS

The rates were negative (tissue loss) for the abdomen and thigh (d4T+3TC, ZDV+3TC) and triceps (ZDV+3TC) skinfolds. For ABC+3TC, most rates were positive (tissue gain). No differences among regimens were seen for the rates of change in the subscapular or suprascapular skinfolds. Rates in the early period were generally positive. The late period rates were negative for d4T+3TC and ZDV+3TC and significantly different from 0 for the abdomen and thigh (d4T+3TC, ZDV+3TC) and triceps (ZDV+3TC) skinfolds, whereas ABC+3TC had less loss in the late period. Most early versus late differences were significant for d4T+3TC and ZDV+3TC; only the triceps skinfold was significant for ABC+3TC.

CONCLUSIONS

In this prospective nonrandomized evaluation, subcutaneous tissue changes varied by regimen. Similar losses were demonstrated for d4T+3TC and ZDV+3TC, whereas ABC+3TC had gains. Temporal differences in rates for d4T+3TC and ZDV+3TC suggest initial recovery followed by long-term treatment effect.

Protease inhibitors (PIs) are widely assumed to be associated with a syndrome of insulin resistance accompanied by hyperlipidemia and fat redistribution. Insulin resistance in HIV infection has numerous other causes, however, which include not only the direct effects of antiretroviral drugs but also factors such as aging and restoration to health accompanied by fat accumulation. Studies of PIs in HIV-infected and noninfected patients indicate that some of these drugs are associated with reduced insulin sensitivity (greater acute versus chronic effects) that may be due to direct blockade of the insulin-sensitive glucose transporter in muscle and fat cells. Other studies have shown that insulin levels increase over time with antiretroviral therapy, likely the result of improved health, fat accumulation, and aging, and that increases in visceral fat and upper trunk fat are associated with a higher risk of insulin resistance in HIV-infected and -uninfected individuals alike. This article summarizes a presentation on insulin resistance in HIV infection made by Carl Grunfeld, MD, PhD, at the 10th Annual Ryan White HIV/AIDS Program Clinical Update in Phoenix in June 2007.

Inflammation produces marked changes in lipid metabolism, including increased serum fatty acids (FAs) and triglycerides (TGs), increased hepatic TG production and VLDL secretion, increased adipose tissue lipolysis, and decreased FA oxidation in liver and heart. Lipopolysaccharide (LPS) also increases TG and cholesteryl ester levels in kidneys. Here we confirm these findings and define potential mechanisms. LPS decreases renal FA oxidation by 40% and the expression of key proteins required for oxidation of FAs, including FA transport protein-2, fatty acyl-CoA synthase, carnitine palmitoyltransferase-1, medium-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase. Similar decreases were observed in peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice. LPS also caused a reduction in renal mRNA levels of PPARalpha (75% decrease), thyroid hormone receptor alpha (TRalpha) (92% decrease), and TRbeta (84% decrease), whereas PPARbeta/delta and gamma were not altered. Expression of PGC1 alpha and beta, coactivators required for PPARs and TR, was also decreased in kidneys of LPS-treated mice, as were mitochondrial genes regulated by PGC1 (Atp5g1, COX5a, Idh3a, and Ndufs8). Decreased renal FA oxidation could be a by-product of the systemic coordinated host response to increase FAs and TGs available for host defense and/or tissue repair. However, the kidney requires energy to support its transport functions, and the inability to generate energy via FA oxidation might contribute to the renal failure seen in severe sepsis.

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here, we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased. We therefore explored the effect of LPS on PCSK9 expression. LPS results in a marked increase in hepatic PCSK9 mRNA levels (4h 2.5-fold increase; 38h 12.5-fold increase). The increase in PCSK9 is a sensitive response with 1microg LPS inducing a (1/2) maximal response. LPS also increased PCSK9 expression in the kidney. Finally, zymosan and turpentine, other treatments that induce inflammation, also stimulated hepatic expression of PCSK9. Thus, inflammation stimulates PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense.

Infection and inflammation affect adipose triglyceride metabolism, resulting in increased plasma free fatty acid (FFA) and VLDL levels during the acute-phase response. Lipin-1, a multifunctional protein, plays a critical role in adipose differentiation, mitochondrial oxidation, and triglyceride synthesis. Here, we examined whether LPS [a Toll-like receptor (TLR)-4 activator], zymosan (a TLR-2 activator), and proinflammatory cytokines regulate lipin-1 in adipose tissue. LPS administration caused a marked decrease in the levels of lipin-1 mRNA and protein in adipose tissue. The decrease in lipin-1 mRNA levels occurred rapidly and lasted for at least 24 h. In contrast, lipin-2 and -3 mRNA levels did not change, suggesting specific repression of lipin-1. Zymosan similarly decreased lipin-1 mRNA without affecting lipin-2 or lipin-3 mRNA levels. To determine the pathways by which LPS repressed lipin-1, we examined the effect of proinflammatory cytokines on cultured adipocytes. In 3T3-L1 adipocytes, TNF-alpha, IL-1beta, and IFN-gamma, but not LPS or IL-6, caused a decrease in lipin-1 mRNA levels. Furthermore, TNF-alpha and IL-1beta administration also decreased mRNA levels of lipin-1 in adipose tissue in mice. Importantly, the LPS-induced decrease in lipin-1 mRNA levels was significantly but not totally blunted in TNF-alpha/IL-1 receptor-null mice compared with controls, suggesting key roles for TNF-alpha/IL-1beta and other cytokines in mediating LPS-induced repression of lipin-1. Together, our results demonstrate that expression of lipin-1, one of the essential triglyceride synthetic enzymes, was suppressed by LPS, zymosan, and proinflammatory cytokines in mouse adipose tissue and in cultured 3T3-L1 adipocytes, which could contribute to a decrease in the utilization of FFA to synthesize triglycerides in adipose tissue, thus promoting the release of FFA into the circulation.