The Roles of Genetic Polymorphisms and Human Immunodeficiency Virus Infection in Lipid Metabolism

Figure 2

The dyslipidemia associated with protease inhibitor (PI) is characterized by decreased plasma high-density lipoprotein cholesterol (HDL-C) and increased total cholesterol, triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C), which together constitute a highly atherogenic lipid profile. Several mechanisms are proposed such that: (1) the PI-induced dyslipidemia is based upon the structural similarity with the amino acid sequence of the C-terminal region of cytoplasmic retinoic acid-binding protein type 1 (CRABP-1). The PI likely binds to CRABP-1, increasing apoptosis and diminishing the proliferation of peripheral adipocytes; (2) PI suppresses the proteasome-mediated degradation of sterol regulatory element binding proteins (nSREBP) in the liver and adipocytes. These transcription factors stimulate fatty acid and TG synthesis in the liver and adipose tissue and control several steps of cholesterol synthesis. The hepatic accumulation of nSREBP increases TG and cholesterol biosynthesis, whereas accumulation in adipose tissue causes insulin resistance reduced leptin expression and lipodystrophy; (3 and 4) PI-induced dyslipidemia is also based on the structural similarity between the catalytic region of HIV-1 protease and the LDL-receptor-related protein (LRP) and interferes with LRP-LPL complex formation, as a result it reduces the adipose storage capacity and increases plasma TG-rich lipoproteins; (5) PI also increases the expression and secretion of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), which are involved in altered adipocyte functions and decreased adiponectin; and (6) PI increases the hepatic synthesis of TG, very-low density lipoprotein cholesterol (VLDL-C), and to a lesser extent, cholesterol.