The role of C/EBP homologous protein in HIV protease inhibitor‐induced dyslipidemia

Association of HIV protease inhibitors (PIs) with metabolic abnormalities is a major concern for long‐term use of HIV PIs in the treatment of HIV infection. We have previously shown that endoplasmic reticulum (ER) stress is a major cellular mechanism underlying HIV PI‐induced dyslipidemia. The C/EBP homologous protein (CHOP) is a key transcriptional factor involved in ER stress–mediated apoptosis. In this study, we specifically examined the role of CHOP in HIV PI‐induced dyslipidemia. Methods Primary hepatocytes isolated from wild type and CHOP −/− mice were used in in vitro studies. Wild type and CHOP −/− mice were used in in vivo studies. Lipid accumulation was detected by Oil Red O staining and HE staining. The mRNA levels of key genes involved in hepatic lipid metabolism were determined by real‐time RT‐PCR. Results HIV PI‐induced intracellular lipid accumulation was significantly reduced in the absence of CHOP. Treatment of wild type mice with HIV PIs for four weeks significantly increased serum levels of triglycerides (TG) and free cholesterol (FC) and induced lipid accumulation in the liver. However, CHOP −/− mice had low serum TG and FC levels and less lipid accumulation in the liver under the same treatment. In addition, HIV PI‐induced upregulation of HMG‐CoA‐reductase, SREBP‐1, and hepatic lipase was attenuated in CHOP −/− mice. Conclusion CHOP plays a critical role in HIV PI‐induced dyslipidemia.