Strong induction of PCSK9 gene expression through HNF1α 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...
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doaj-c37158b904c2448c9eeeb3023ae871302021-04-28T06:04:12ZengElsevierJournal of Lipid Research0022-22752010-06-0151614861495Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamstersBin Dong0Minhao Wu1Hai Li2Fredric B. Kraemer3Khosrow Adeli4Nabil G. Seidah5Sahng Wook Park6Jingwen Liu7Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304The Hospital for Sick Children, University of Toronto, Toronto, Ontario, CanadaLaboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, CanadaInstitute of Genetic Science, Brain Korea 21 Project, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-Ku, Seoul 120-752, Republic of KoreaDepartment of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304We 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 α (HNF1α), the newly identified key transactivator for PCSK9 gene expression. Our study suggests that the inducing effect of rosuvastatin on HNF1α is likely a underlying mechanism accounting for the higher induction of PCSK9 than LDLR because of the utilization of two transactivators (HNF1α 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.http://www.sciencedirect.com/science/article/pii/S0022227520410235LDL receptorrosuvastatinberberine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bin Dong Minhao Wu Hai Li Fredric B. Kraemer Khosrow Adeli Nabil G. Seidah Sahng Wook Park Jingwen Liu |
spellingShingle |
Bin Dong Minhao Wu Hai Li Fredric B. Kraemer Khosrow Adeli Nabil G. Seidah Sahng Wook Park Jingwen Liu Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters Journal of Lipid Research LDL receptor rosuvastatin berberine |
author_facet |
Bin Dong Minhao Wu Hai Li Fredric B. Kraemer Khosrow Adeli Nabil G. Seidah Sahng Wook Park Jingwen Liu |
author_sort |
Bin Dong |
title |
Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters |
title_short |
Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters |
title_full |
Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters |
title_fullStr |
Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters |
title_full_unstemmed |
Strong induction of PCSK9 gene expression through HNF1α and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters |
title_sort |
strong induction of pcsk9 gene expression through hnf1α and srebp2: mechanism for the resistance to ldl-cholesterol lowering effect of statins in dyslipidemic hamsters |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2010-06-01 |
description |
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 α (HNF1α), the newly identified key transactivator for PCSK9 gene expression. Our study suggests that the inducing effect of rosuvastatin on HNF1α is likely a underlying mechanism accounting for the higher induction of PCSK9 than LDLR because of the utilization of two transactivators (HNF1α 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. |
topic |
LDL receptor rosuvastatin berberine |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520410235 |
work_keys_str_mv |
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