title: Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) impedes low‑density lipoprotein (LDL) receptor (LDLR)-mediated LDL-cholesterol uptake and has hence emerged as a critical regulator of serum cholesterol levels and a new therapeutic target for the treatment of hypercholesterolemia. Statins have been shown to elevate circulating PCSK9 levels by stimulating PCSK9 gene transcription, which reduces the clinical efficacy of statin in LDL‑cholesterol reduction. The transcription of PCSK9 is partially controlled by the hepatocyte nuclear factor 1 (HNF1) binding site embedded in the proximal region of its promoter. In this study, we utilized adenoviral shRNA delivery vectors to generate liver-specific knockdown of HNF1α (Ad‑shHNF1α) or HNF1β (Ad‑shHNF1β) in hamsters to examine the impact of reduced hepatic expression of HNF1 transcription factors on statin‑induced elevation of PCSK9 expression and serum cholesterol levels. We showed that the administration of rosuvastatin (RSV) to normolipidemic hamsters significantly augmented hepatic PCSK9 expression and serum PCSK9 levels. In addition, RSV treatment increased hepatic HNF1α protein levels without a clear effect on HNF1α mRNA expression. Injection of Ad-shHNF1α or Ad‑shHNF1β into hamsters both blunted RSV‑induced elevation of PCSK9 serum concentration and hepatic mRNA and protein levels, which led to significant increases in liver LDLR protein abundance. Furthermore, hepatic depletion of HNF1 factors lowered circulating total cholesterol and non‑high density lipoprotein cholesterol levels in RSV‑treated hamsters. Our study demonstrates that both HNF1α and HNF1β are positive regulators of hepatic PCSK9 transcription in hamster species and that transient, liver-specific knockdown of either HNF1α or HNF1β could antagonize the RSV‑induced elevation of serum PCSK9 and reduce circulating cholesterol levels.
authors.affiliation: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Amar Bahadur
authors.initials: AB
authors.lastname: Singh
authors.affiliation: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Vikram Ravindra
authors.initials: VR
authors.lastname: Shende
authors.affiliation: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood; D003001:Cloning, Molecular; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D051537:Hepatocyte Nuclear Factor 1 / Q000235:genetics / Q000378:metabolism*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D000071449:Proprotein Convertase 9 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism; D000068718:Rosuvastatin Calcium / Q000494:pharmacology*; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D000071449:Proprotein Convertase 9