In the fasted state, HARS is characterized by an excessive FFA release by adipocyte lipolysis, resulting in a greater net delivery of FFA to the plasma, ultimately resulting in greater hepatic delivery and export as triglyceride-rich very low density lipoprotein (VLDL) leading to hypertriglyceridemia[22, 41, 42]. In the fed state, a different mechanism results in a second contribution to the hypertriglyceridemia associated with HARS. Examination of the disposal of labeled triglyceride from the plasma chylomicron pool in HARS patients showed a marked retardation of the labeled fatty acids from the chylomicrons compared to controls. Further, of the small amount cleared, a greater proportion of the released FFA was found within the plasma rather than taken into the adipocyte in HARS patients suggesting that there was an adipocyte defect resulting in impaired fat storage .
The mechanism underlying lipodystrophy may involve the regulation of adipocyte hormone-sensitive lipase; the result is an accelerated rate of whole-body lipolysis that facilitates the "redistribution" of fat. Results of a study in men with both peripheral fat loss and central fat accumulation, as well as dyslipidemia suggested that a regulatory defect in adipocyte lipolysis could account for both the dyslipidemia and the peripheral fat loss . Hyperlipolytic activity and increased release of FFAs would promote processes for which fatty acids are substrates, for example, the hepatic extraction and conversion to glycerolipids. This mechanism could explain the hypertriglyceridemia seen in HIV-infected patients with lipodystrophy, but does not explain the central adiposity seen in some of them. The authors conjecture that either decreased lipolysis or increased deposition of fatty acids outstripping lipolysis in visceral fat depots might account for the observed central adiposity . This is further discussed below.
Sekhar and colleagues have posited a basic defect in fatty acid metabolism in peripheral adipocytes in HARS patients to account for: the acceleration in lipolysis (primarily in the femoral-gluteal region), release of fatty acids for hepatic re-esterification leading to hypertriglyceridemia, along with decreased clearance of chylomicron triglyceride. The greater availability of fatty acids increases uptake by the visceral adipocytes, which have a higher lipid turnover rate than peripheral adipocytes, favoring greater net deposition of fat and the development of central adiposity. The underlying causal factor may be the HAART agents or proteins expressed by the virus itself. The net result is increased triglyceride deposition in the liver, central fat, and skeletal muscle; and an increase in proatherogenic lipoproteins or "systemic steatosis".
In this "systemic steatosis" model, increased uptake of fatty acids in the liver promotes the synthesis of triglycerides and apolipoprotein B, reduces degradation of apolipoprotein B, and leads to hypertriglyceridemia due to increased production of VLDL. Lipid uptake within the central fat depots is higher than in peripheral fat depots (femoral-gluteal regions). High fat diets cause overexpression of the endothelial cell enzyme lipoprotein lipase, which hydrolyzes lipids in lipoproteins. The differential lipid uptake in the "systemic steatosis" model may therefore be due to an increased sensitivity to lipoprotein lipase-activating hormones (e.g. cortisol in omental adipocytes), thus sequestering fatty acids as di- and tri-glycerides in abdominal visceral depots.
Implications of Fatty Acid Blockade
Inhibition of peripheral lipolysis improves insulin sensitivity in protease inhibitor-treated men with signs of lipodystrophy. On the assumption that increased circulating fatty acids contribute to hepatic insulin resistance and decreased insulin signaling through insulin receptor substrate, Hadigan and colleagues investigated the effects of acute lipolytic blockade with the nicotinic acid analog acipimox, which inhibits fatty acid release. Patients in this study had significant central adiposity (body mass index 28.8 ± 1.9 kg/m2; extremity fat 15.9 ± 2.4%; trunk fat 25.8 ± 2.2%; VAT 156.3 ± 2.8 cm2; waist-to-hip ratio [WHR] 0.99 ± 0.01). Six of the seven subjects who received acipimox showed improvement in the insulin sensitivity index; and fatty acid area under the curve correlated inversely with insulin sensitivity (r = -0.75, P < 0.05) . More recently, Hadigan et al. reported on the 3-month use of acipimox in HIV-infected men and women with hypertriglyceridemia. Acipimox led to a significant sustained reduction in FFA, decreased rates of lipolysis, and a 34 mg/dL mean reduction in triglyceride concentration and improved insulin sensitivity at 3 months. This supports the concept that excessive release of fatty acids contributes to hepatic adiposity and systemic insulin resistance.
A Consequence of Immune Reconstitution
HIV causes immune dysregulation and immune deficiency; either or both may play a role in fat redistribution. It could be due to the partial immune reconstitution that occurs from successful therapy, or there may be an abnormal immune response to therapy. When CD4 levels start to return to normal after effective HIV therapy, the immune system is not normalized; some patients still experience an opportunistic illness. It is possible that perhaps an immune system continues to be "turned on", to respond to HIV that is no longer detectable, and attacks and kills subcutaneous fat cells–immune reconstitution syndrome. The apoptotic subcutaneous adipose cells would no longer serve as a viable storage depot for triglycerides and FFAs. The atrophic SAT may also release FFAs, which could find their way to VAT. Mitochondrial toxicity due to antiretroviral medication or the HIV itself could result in fat apoptosis. Many potential explanations are being offered, but research has yet to fully elucidate this phenomenon. Though HAART normally induces immune reconstitution, a problem can arise when the immune reconstitution is excessive or inappropriate.