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      Sirolimus modifies cholesterol homeostasis in hepatic cells: a potential molecular mechanism for sirolimus-associated dyslipidemia.

      Transplantation
      Cell Line, Cholesterol, LDL, metabolism, Dyslipidemias, chemically induced, Endoplasmic Reticulum, chemistry, Golgi Apparatus, Hepatocytes, drug effects, Homeostasis, Humans, Immunosuppressive Agents, adverse effects, pharmacology, Intracellular Signaling Peptides and Proteins, analysis, antagonists & inhibitors, Membrane Proteins, Protein Transport, RNA, Messenger, Receptors, LDL, genetics, Sirolimus, Sterol Regulatory Element Binding Protein 2

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          Abstract

          Sirolimus is a potent immunosuppressive agent, which is associated with dyslipidemia in clinical transplantation. The present study was undertaken to investigate the potential hepatocyte mechanisms by which sirolimus causes dyslipidemia. Using both a quantitative assay of intracellular cholesterol and an [3H]-labeled cholesterol efflux assay, we studied the effect of sirolimus on cholesterol accumulation and cholesterol efflux in HepG2 cells in the absence or presence of inflammatory stress induced by interleukin-1beta. The gene and protein expression of molecules involved in cholesterol homeostasis were examined by real-time reverse-transcription polymerase chain reaction and Western blotting. Sirolimus inhibited low-density lipoprotein (LDL) receptor (LDLr)-mediated cholesterol ester accumulation induced by interleukin-1beta in HepG2 cells. This inhibitory effect was mediated by down-regulation of sterol regulatory element-binding proteins (SREBP) cleavage activating protein (SCAP) and SREBP-2 mRNA expression. Using confocal microscopy, we demonstrated that sirolimus reduced translocation of SCAP-SREBP2 complex from endoplasmic reticulum to Golgi for activation, thereby inhibiting LDLr gene transcription. Reduction of LDLr in the liver may result in a delay of LDL-cholesterol clearance from circulation causing an increase of plasma cholesterol concentration. Furthermore, sirolimus increased cholesterol efflux mediated by adenosine triphosphate-binding cassette transporter A1 gene expression by increasing peroxisome proliferator-activated receptor-alpha and liver X receptor-alpha gene and protein expression. Increased cholesterol efflux from HepG2 cells may increase high-density lipoprotein cholesterol level and also contribute to apolipoprotein B lipoprotein formation by enhancing transfer of high-density lipoprotein cholesterol to apolipoprotein B lipoproteins. This study demonstrates that the increase of LDL cholesterol by sirolimus is partly due to the reduction of LDLr on hepatocytes.

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