The molecular mechanism of the induction of the low density lipoprotein receptor by chenodeoxycholic acid in cultured human cells.
In a cultured human hepatoblastoma cell line, Hep G2, chenodeoxycholic acid (CDCA) induced LDL receptor mRNA levels approximately 4 fold and mRNA levels for HMG-CoA reductase and HMG-CoA synthase two fold. In contrast, the mRNA levels for mevalonate kinase, farnesyl pyrophosphate synthase and squalene synthase were not changed significantly. The pattern of the induction of the sterol-sensitive genes was similar to the induction by N-acetyl-leucyl-leucyl-norleucinal (ALLN), an SREBP degradation inhibitor, suggesting that CDCA may increase mature SREBPs. CDCA could inhibit the 25-hydroxycholesterol mediated inactivation of SREBP without affecting mRNA levels of SREBPs. These results suggest that CDCA can affect sterol metabolism by a novel mechanism involving the inhibition of the oxysterol-mediated inactivation of SREBP.
Kawabe
Y
Y
Third Department of Internal Medicine, University of Tokyo, Japan.
Shimokawa
T
T
Matsumoto
A
A
Honda
M
M
Wada
Y
Y
Yazaki
Y
Y
Endo
A
A
Itakura
H
H
Kodama
T
T
D019883:Alkyl and Aryl Transferases; D001483:Base Sequence; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D003062:Codon; D004268:DNA-Binding Proteins / Q000378:metabolism; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D051228:Geranyltranstransferase; D018197:Hepatoblastoma; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000096:biosynthesis*; D007976:Leupeptins / Q000494:pharmacology; D008113:Liver Neoplasms; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011973:Receptors, LDL / Q000096:biosynthesis*; D012045:Regulatory Sequences, Nucleic Acid; D014166:Transferases / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D003062:Codon; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D007976:Leupeptins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; D002635:Chenodeoxycholic Acid; C063261:acetylleucyl-leucyl-norleucinal; C007997:25-hydroxycholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D014166:Transferases; D006904:Hydroxymethylglutaryl-CoA Synthase; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase