Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters.
We investigated the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the resistance of dyslipidemic hamsters to statin-induced LDL-cholesterol (LDL-C) reduction and the molecular mechanism by which statins modulated PCSK9 gene expression in vivo. We utilized the fructose diet-induced dyslipidemic hamsters as an in vivo model and rosuvastatin to examine its effects on liver PCSK9 and LDL receptor (LDLR) expression and serum lipid levels. We showed that rosuvastatin induced PCSK9 mRNA to a greater extent than LDLR mRNA in the hamster liver. The net result was that hepatic LDLR protein level was reduced. This correlated closely with an increase in serum LDL-C with statin treatment. More importantly, we demonstrated that in addition to an increase in sterol response element binding protein 2 (SREBP2) expression, rosuvastatin treatment increased the liver expression of hepatocyte nuclear factor 1 alpha (HNF1alpha), the newly identified key transactivator for PCSK9 gene expression. Our study suggests that the inducing effect of rosuvastatin on HNF1alpha is likely a underlying mechanism accounting for the higher induction of PCSK9 than LDLR because of the utilization of two transactivators (HNF1alpha and SREBP2) in PCSK9 transcription versus one (SREBP2) in LDLR transcription. Thus, the net balance is in favor of PCSK9-induced degradation of LDLR in the hamster liver, abrogating the effect of rosuvastatin on LDL-C lowering.
Dong
Bin
B
Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Wu
Minhao
M
Li
Hai
H
Kraemer
Fredric B
FB
Adeli
Khosrow
K
Seidah
Nabil G
NG
Park
Sahng Wook
SW
Liu
Jingwen
J
D000818:Animals; D002460:Cell Line; D008078:Cholesterol, LDL / Q000097:blood; D006224:Cricetinae; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology; D005632:Fructose / Q000009:adverse effects; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D012697:Serine Endopeptidases / Q000235:genetics*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
D008078:Cholesterol, LDL; D004040:Dietary Carbohydrates; D005464:Fluorobenzenes; D051538:Hepatocyte Nuclear Factor 1-alpha; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D013449:Sulfonamides; D005632:Fructose; D000068718:Rosuvastatin Calcium; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases