Role of JNK and c-Jun signaling pathway in regulation of human serum paraoxonase 1 gene transcription by berberine in human HepG2 cells.
Human serum paraoxonase 1 (PON1), an arylesterase, is associated with high-density lipoprotein (HDL) and can inhibit the oxidative modification of low-density lipoprotein (LDL), implying that PON1 may prevent atherosclerosis. Berberine, a botanical alkaloid, lowers the cholesterol level in serum and is thought to display cardioprotective properties. However, the effect of berberine on PON1 gene expression remains unclear. Thus, we evaluated how berberine regulates PON1 gene expression. In human hepatoma HepG2 and Huh7 cells, the PON1 protein levels were increased by berberine in a dose- and time-dependent manner. Data from real time PCR analysis indicated that berberine could up-regulate PON1 expression at the transcriptional level. Additionally, treating HepG2 cells with berberine increased the levels of phosphorylated JNK and its downstream target c-Jun. The PON1 upstream region contained a consensus binding site for AP1, and the electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that the AP1 factors, especially c-Jun, bind to the upstream sequence of the PON1 promoter upon berberine treatment. Moreover, pretreatment with SP600125 (JNK inhibitor) or curcumin (AP-1 inhibitor) markedly attenuated the berberine-induced PON1 promoter activity and protein expression. This is the first study to suggest that JNK/c-Jun signalling pathway plays a crucial role in berberine-regulated PON1 transcription in human hepatoma cells. The induction of PON1 by berberine elucidates a potential mechanism through which berberine may protect against atherosclerosis.
Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
Chi-Chih
CC
Cheng
Chi-Mei
CM
Hsueh
Kae-Woei
KW
Liang
Chih-Tai
CT
Ting
Chi-Luan
CL
Wen
Shih-Lan
SL
Hsu
D043303:Aryldialkylphosphatase / Q000096:biosynthesis* / Q000235:genetics; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D001599:Berberine; D048031:JNK Mitogen-Activated Protein Kinases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human