doi: 10.1161/01.ATV.0000198749.28422.29
© 2006 American Heart Association, Inc.
Editorials |
HIV Protease Inhibitors and Hyperlipidemia
A Fatty Acid Connection
From the Departments of Biochemistry and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City.
Correspondence to Arthur A. Spector, Department of Biochemistry 4-403 BSB, University of Iowa, Iowa City, IA 52242. E-mail arthur-spector{at}uiowa.edu
Treatment with a combination of highly active antiretroviral agents considerably reduces the morbidity and mortality of human immunodeficiency virus (HIV) infection.1 Although the clinical benefits are considerable, the protease inhibitors contained in these antiretroviral regimens produce a lipodystrophy syndrome characterized by changes in body fat distribution, hyperlipidemia, and insulin resistance.2 The hyperlipidemia is attributable to increases in very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), and it can produce serious cardiovascular complications including endothelial dysfunction and atherosclerosis.3,4
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A number of studies indicate that the hyperlipidemia produced by HIV protease inhibitors is attributable to an increase in VLDL production. Data from HIV positive patients indicate that excessive free fatty acid (FFA) mobilization occurs because of insulin resistance in the adipose tissue,5 resulting in increased VLDL–triglyceride production and apoB synthesis. Likewise, studies in C57BL/6 mice treated with HIV protease inhibitors demonstrate increased VLDL-triglyceride production and apoB synthesis,6 and increased triglyceride synthesis also was observed in HepG2 cells and AKR/J mice incubated with protease inhibitors.7 The hyperlipidemia in the mice was attributed to elevated fatty acid and cholesterol synthesis in the liver and adipose tissue caused by activation of sterol regulatory element binding protein (SREBP) 1 and 2,8 whereas studies in cultured liver cells suggest that the mechanism involves decreased degradation of nascent apoB attributable to inhibition of the 20S proteasome.9
There is also evidence that HIV protease inhibitors do not reduce the clearance of either VLDL or triglyceride-rich lipoprotein remnants,5,6,10 providing additional support for a mechanism based on increased VLDL production. However, other studies indicate that impaired lipoprotein clearance contributes to the hyperlipidemia. For example, two enzymes involved in lipoprotein–triglyceride removal, lipoprotein lipase and hepatic lipase, were found to be decreased in HIV patients treated with protease inhibitors.11 A reduction in triglyceride-rich lipoprotein clearance after a high-fat meal also has been observed in treated HIV patients.12
What can account for these conflicting results? Are they attributable to clinical variability, differences in drug regimen, or differences in the animal and cell models that have been tested? In an article in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, den Boer et al attempt to resolve these questions by investigating the mechanism of action of the protease inhibitor ritonavir in female APOE*3-Leiden transgenic mice fed a Western-type diet.13 The APOE*3-Leiden experimental model was selected because these mice have a lipoprotein profile similar to that of humans, are susceptible to diet- and drug-induced hyperlipidemia and atherosclerosis, and are sensitive to treatment with hypolipidemic drugs.
Ritonavir is a peptidomimetic agent that inhibits the HIV-1 and HIV-2 proteases. As a result, the gag-pol polypeptide precursor cannot be processed, and the HIV particles that are formed are immature and not infectious. However, a complication of ritonavir therapy is hyperlipidemia that can be severe enough to cause acute pancreatitis.14 den Boer et al find that there is no increase in VLDL production in the APOE*3-Leiden mice treated with ritonavir. Instead, the hyperlipidemia is attributable to inhibition of plasma triglyceride clearance, associated with a 44% decrease in post-heparin lipoprotein lipase activity. This is consistent with previous data indicating that the hyperlipidemia is caused by a reduction in VLDL–triglyceride clearance.11,12 Furthermore, den Boer et al report two new findings that provide insight into the mechanism of the clearance defect. One is that the reduction in triglyceride fatty acid incorporation is localized to adipose tissue of the APOE*3-Leiden mice. The other, which is unexpected, is that ritonavir reduces the incorporation of plasma FFA into the adipose tissue to the same extent as fatty acid derived from plasma triglycerides.13 This implies that the inhibitory effect involves adipose tissue fatty acid use, a mechanism that can account for both the hyperlipidemia and lipodystrophy produced by HIV protease inhibitors.
These results should be considered in the context of the fatty acid use mechanism illustrated in the Figure. Fatty acid is supplied to tissues primarily in two forms, triglyceride-rich lipoproteins and FFA transported by plasma albumin.15 Fatty acids are hydrolyzed from the lipoprotein triglycerides by lipoprotein lipase, and the FFA dissociates from albumin before uptake. The fatty acid derived from both sources then moves across the cell membrane either by facilitated transport or diffusion through the lipid bilayer.16,17 A cytoplasmic fatty acid binding protein (FABP) facilitates the desorption of the fatty acid from the inner leaflet of the cell membrane,18 and the fatty acid is converted to an acylcoenzyme A derivative and either oxidized or incorporated into tissue lipids. As opposed to other tissues, adipose tissue does not incorporate net quantities of plasma FFA under physiological conditions. Therefore, the FFA results indicate that ritonavir inhibits adipose tissue use at a step subsequent to the hydrolysis of the lipoprotein triglycerides, not that plasma FFA use is involved in the physiological mechanism. The most likely sites where ritonavir might produce inhibition are the membrane fatty acid transporter, FABP, or the triglyceride synthesis pathway.
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CoA, fatty acylcoenzyme A; FFA, plasma free fatty acid; TG, triglyceride.The effect appears to be selective for adipose tissue because neither FFA nor triglyceride fatty acid incorporation were reduced in liver, heart, or skeletal muscles.13 This suggests that the inhibition may involve either the membrane transporter or FABP because three membrane fatty acid transport proteins and nine FABPs have been identified,17,18 and one or both of these proteins are different in these tissues. CD36, also called FAT, is the membrane fatty acid transport protein in adipocytes,19 and HIV protease inhibitors have been observed to decrease CD36 expression.20 However, a mechanism involving CD36 seems improbable because CD36 also facilitates fatty acid uptake in muscle,19 a tissue where fatty acid incorporation was not affected by ritonavir. The possibility that triglyceride synthesis is inhibited also seems unlikely because other data indicate that diacylglycerol acyltransferase (DGAT), a key enzyme in this pathway, is not inhibited by ritonavir.6
den Boer et al suggest that the reduction in lipoprotein lipase activity in the APOE*3-Leiden mice treated with ritonavir is attributable to product inhibition resulting from an increase in plasma FFA.13,21 However, the FFA increase was only 16%, and albumin probably has enough binding capacity to accommodate such a small increase even if competitive binding between ritonavir and FFA occurs.
The extent to which these results obtained in the APOE*3-Leiden transgenic mouse can be applied to the action of protease inhibitors in HIV-infected patients is questionable. Nevertheless, the novel finding that ritonavir selectively inhibits adipose tissue fatty acid incorporation is striking and warrants further investigation. To begin to understand the biochemical basis, it is important to determine whether the effect on adipose tissue occurs at the level of membrane transport, binding to FABP, fatty acid activation, or triglyceride synthesis. Furthermore, the selectivity for adipose tissue suggests the possible involvement of peroxisome proliferator-activated receptor (PPAR) 
. In this regard, Carr et al have hypothesized that HIV-protease inhibitors indirectly decrease PPAR function by inhibiting the synthesis and intracellular transport of 9-cis-retinoic acid, thereby reducing the amount of activated retinoid x receptor (RXR) available to form the active heterodimer.22 Methods are readily available to test these possibilities, and the resulting information will provide new insight into the mechanism of the hyperlipidemia produced by HIV protease inhibitors as well as the factors that regulate cellular fatty acid utilization.
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Acknowledgments |
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The author is supported by research grant R01 HL072845 from the National Heart, Lung, and Blood Institute, National Institutes of Health.
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Footnotes |
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Street address for express mail delivery only: Bowen Science Building, 51 Newton Road.
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References |
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Arterioscler. Thromb. Vasc. Biol. 2006 26: 124-129.
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