HIV Protease Inhibitor Induces Fatty Acid and Sterol Biosynthesis in Liver and Adipose Tissues Due to the Accumulation of Activated Sterol Regulatory Element-binding Proteins in the Nucleus

Abstract

The mechanism by which human immunodeficiency virus (HIV) protease inhibitor therapy adversely induces lipodystrophy and hyperlipidemia has not been defined. This study explored the mechanism associated with the adverse effects of the prototype protease inhibitor ritonavir in mice. Ritonavir treatment increased plasma triglyceride and cholesterol levels through increased fatty acid and cholesterol biosynthesis in adipose and liver. Ritonavir treatment also resulted in hepatic steatosis and hepatomegaly. These abnormalities, which were especially pronounced after feeding a Western type high fat diet, were due to ritonavir-induced accumulation of the activated forms of sterol regulatory binding protein (SREBP)-1 and -2 in the nucleus of liver and adipose, resulting in elevated expression of lipid metabolism genes. Interestingly, protease inhibitor treatment did not alter SREBP mRNA levels in these tissues. Thus, the adverse lipid abnormalities associated with protease inhibitor therapy are caused by the constitutive induction of lipid biosynthesis in liver and adipose tissues due to the accumulation of activated SREBP in the nucleus.The discovery and use of protease inhibitor therapy has significantly reduced the morbidity and mortality of AIDS as a consequence of HIV 1 infection (1, 2). Unfortunately, the use of HIV protease inhibitors (PI) has also been associated with several undesirable side effects, including peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance (3-7). These abnormalities in lipid metabolism may also lead to the increased incidence of accelerated atherosclerosis in HIV patients (8, 9). The mechanism by which PI therapy leads to lipid abnormalities remains unclear, thus limiting the options for effective treatment of HIV-infected individuals.The urgency of designing agents that are less likely to induce lipid disturbances has prompted numerous studies aimed at understanding the relationship between PI therapy and abnormalities in lipid metabolism and preadipocyte differentiation. However, cell culture studies have yielded conflicting results with the PI either suppressing (10 -12) or enhancing (13) preadipocyte differentiation in vitro. These studies also focused primarily on PI effects on transcription factors that are responsible for regulating lipid metabolism pathways and adipocyte differentiation genes, such as the peroxisome proliferator-activated receptor-␥ (14), the CCAAT/enhancer-binding protein (15), and the sterol regulatory element-binding protein-1 (SREBP-1) (16, 17). Very little attention was paid to PI effects on lipogenesis per se. Accordingly, the lipodystrophic and hyperlipidemic effects of PI in vivo have not been defined. Additionally, the contribution of different dietary nutrients on PIinduced lipid abnormalities has not been addressed.In this study, we examined the effect of ritonavir, a prototype PI that elicits potent lipid abnormalities in patients (18 -20), on lipogenesis and plasma lipid concentrati...

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

“…An upregulation of metabolic pathways leading to an excessive production of VLDL can also be caused by the PI-induced intra-hepatocyte accumulation of nuclear transcription factors involved in the metabolism of apolipoprotein B, such as SRBPs. In addition, the levels of lipoprotein particles containing apolipoprotein C-III and apolipoprotein E are increased in PI-treated patients [176][177][178][179].…”

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

“…Though the ubiquitin-proteosome system for degradation is active during development [53,54], it seems that the SREBPs would not be readily modified and/or degraded during this time of rapid growth since sterol synthesis rates remain relatively active in the presence of cholesterol. Lack of SREBP-2 degradation may be the result of a change in proteosome activity [55] or rate of de-ubiquitination [41].…”

Effectiveness of tipranavir versus darunavir as a salvage therapy in HIV-1 treatment-experienced patients

“…In our study, we did not observe an increase in either ALT or AST levels in the TPV-based regimen, as was observed in the RESIST trials; however, a significant increase in the baseline triglyceride levels through week 24 was observed within groups and after comparison between groups. This finding might be related to the higher dose of boosted ritonavir [13][14][15] detected in the TPV group (400 mg daily) compared with the lesser dose of boosted ritonavir in the DRV group (a higher dose led to an increase in triglycerides).…”