Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression.
Modulation of bile acid synthesis in human by cholestyramine or by chenodeoxycholic acid (CDCA) treatment affects lipoprotein metabolism leading to altered plasma lipid levels. The molecular changes caused by these treatments, which in turn influence lipoprotein metabolism, are still not entirely known in humans. In this study, mRNA levels were analyzed using real time RT-PCR in liver tissue from patients undergoing cholecystectomy due to gallstone disease. The patients were treated with either CDCA (n=6) or cholestyramine (n=5) for three weeks prior to surgery, six patients received no treatment and served as controls. Cholestyramine increased the expression of the LDL receptor (LDLR) by about 65% and that of proprotein convertase subtilisin kexin 9 (PCSK9) by 70%. After CDCA the levels of both LDLR and hydroxy-methyl-glutaryl coenzyme A reductase mRNA decreased approximately by 50%. The expression of PCSK9 was not changed. The mRNA levels of PCSK9, LDLR, and HMGCoAR were significantly correlated to those of sterol regulatory element binding protein 2 (SREBP2), indicating that SREBP2 is of importance in the regulation of the expression of these genes also in human liver.
Nilsson
L-M
LM
Department of Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. lisa-mari.nilsson@ki.se
Abrahamsson
A
A
Sahlin
S
S
Gustafsson
U
U
Angelin
B
B
Parini
P
P
Einarsson
C
C
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D002763:Cholecystectomy; D002792:Cholestyramine Resin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D042882:Gallstones / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001647:Bile Acids and Salts; D005765:Gastrointestinal Agents; D008074:Lipoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002635:Chenodeoxycholic Acid; D002792:Cholestyramine Resin; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases