Rosuvastatin selectively stimulates apolipoprotein A-I but not apolipoprotein A-II synthesis in Hep G2 cells.
Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are extensively used to regulate dyslipidemia and to reduce atherosclerotic cardiovascular disease. In addition to effectively lowering cholesterol and low-density lipoprotein levels, rosuvastatin and certain other statins can also increase plasma high-density lipoprotein (HDL) cholesterol modestly. However, the mechanism of action of rosuvastatin on HDL metabolic processes is not understood. Using cultured human hepatoblastoma cells (Hep G2) as an in vitro model system, we assessed the effect of rosuvastatin on apolipoprotein (apo) A-I and apo A-II (the major proteins of HDL) synthesis and HDL catabolic processes. Rosuvastatin dose-dependently increased messenger RNA expression and de novo synthesis of apo A-I but not apo A-II. Rosuvastatin selectively increased the synthesis of HDL particles containing only apo A-I (LP A-I) but not particles containing both apo A-I and A-II (LP A-I + A-II). The HDL(3)-protein or HDL(3)-cholesterol ester uptake by Hep G2 cells was not affected by rosuvastatin. The apo A-I-containing particles secreted by rosuvastatin-treated Hep G2 significantly increased cholesterol efflux from fibroblasts. The data indicate that rosuvastatin increases hepatic apo A-I but not apo A-II messenger RNA transcription, thereby selectively increasing the synthesis of functionally active apo A-I-containing HDL particles, which mediate cholesterol efflux from peripheral tissues. We suggest that this mechanism of action of rosuvastatin to increase apo A-I production without apo A-I/HDL removal may result in increased apo A-I turnover that results in accelerated reverse cholesterol transport.
Qin
Shucun
S
Department of Veterans Affairs Healthcare System, Atherosclerosis Research Center, Long Beach, CA 90822, USA.
Koga
Takafumi
T
Ganji
Shobha H
SH
Kamanna
Vaijinath S
VS
Kashyap
Moti L
ML
D016632:Apolipoprotein A-I / Q000096:biosynthesis*; D016633:Apolipoprotein A-II / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D008076:Cholesterol, HDL / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D008076:Cholesterol, HDL; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium