Barbaro Giuseppe
Cardiology Unit, Department of Medical Pathophysiology, University La Sapienza, Rome, Italy.
Curr Pharm Des. 2007;13(21):2208-13. doi: 10.2174/138161207781039661.
HIV-associated lipodystrophy or lipoatrophy, unreported before the introduction of highly active antiretroviral therapy (HAART), was first described in 1998, and has a prevalence ranging from 18% to 83%. As in genetic lipodystrophy syndromes, fat redistribution may precede the development of metabolic complications (dyslipidemia, insulin resistance) in HIV-infected patients receiving HAART. The pathogenesis of HAART-associated lipodystrophy and metabolic syndrome is complex and a number of factors are involved, including direct effects of HAART on lipid metabolism, endothelial and adipocyte cell function, and mitochondria. Protease inhibitors are responsible for a decrease in cytoplasmic retinoic-acid protein-1, in low density lipoprotein-receptor-related protein and in peroxisome proliferator activated receptor type-gamma. Nucleoside reverse transcriptase inhibitors, and thymidine analogues, are responsible for mitochondrial dysfunction as demonstrated by a decrease in subcutaneous adipose tissue mitochondrial DNA content. Both phenomena are responsible for a decreased differentiation of adipocytes, increased levels of free fatty acids and lipoatrophy. The increased levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-6 may further contribute in development of lipodystrophy. TNF-alfa activates 11-beta-hydroxysteroid dehydrogenase type-1, which converts inactive cortisone to active cortisol, resulting in increased lipid accumulation in adipocytes and insulin resistance. HAART drugs and inflammatory cytokines are associated with a decrease in adiponectin. The levels of adiponectin and adiponectin-to-leptin ratio correlate positively with insulin resistance in HIV-infected patients with lipodystrophy. HAART-associated metabolic syndrome is an increasingly recognized clinical entity. The atherogenic profile of this syndrome may increase the risk of cardiovascular disease even in young HIV-infected patients. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients receiving HAART.
与人类免疫缺陷病毒（HIV）相关的脂肪代谢障碍或脂肪萎缩，在高效抗逆转录病毒治疗（HAART）出现之前未见报道，于1998年首次被描述，其患病率在18%至83%之间。与遗传性脂肪代谢障碍综合征一样，在接受HAART的HIV感染患者中，脂肪重新分布可能先于代谢并发症（血脂异常、胰岛素抵抗）的发生。HAART相关脂肪代谢障碍和代谢综合征的发病机制复杂，涉及多种因素，包括HAART对脂质代谢、内皮细胞和脂肪细胞功能以及线粒体的直接影响。蛋白酶抑制剂导致细胞质视黄酸蛋白-1、低密度脂蛋白受体相关蛋白和γ型过氧化物酶体增殖物激活受体减少。核苷类逆转录酶抑制剂和胸腺嘧啶类似物导致线粒体功能障碍，皮下脂肪组织线粒体DNA含量减少即证明了这一点。这两种现象均导致脂肪细胞分化减少、游离脂肪酸水平升高和脂肪萎缩。促炎细胞因子水平升高，如肿瘤坏死因子（TNF）-α和白细胞介素-6，可能进一步促使脂肪代谢障碍的发展。TNF-α激活11-β-羟类固醇脱氢酶1型，该酶将无活性的可的松转化为有活性的皮质醇，导致脂肪细胞中脂质蓄积增加和胰岛素抵抗。HAART药物和炎性细胞因子与脂联素减少有关。在患有脂肪代谢障碍的HIV感染患者中，脂联素水平和脂联素与瘦素的比值与胰岛素抵抗呈正相关。HAART相关代谢综合征是一个越来越被认可的临床实体。即使在年轻的HIV感染患者中，该综合征的动脉粥样硬化特征也可能增加心血管疾病的风险。更好地理解导致该综合征的分子机制将有助于发现新药物，从而降低接受HAART的HIV感染患者中脂肪代谢障碍及相关代谢并发症的发生率。
