Sahng Wook Park
@medicine.yonsei.ac.kr
Biochemistry and Molecular Biology
Yonsei University College of Medicine
RESEARCH, TEACHING, or OTHER INTERESTS
Biochemistry (medical)
Scopus Publications
Scopus Publications
Sun-Ho Lee, Gibbeum Lim, Hyoeun Kim, David Suh, Hyo-Kyoung Choi, Hyoung-Pyo Kim, Ho-Geun Yoon, Sahng Wook Park, Seok-Min Kang, Chulan Kwon,et al.
Elsevier BV
Ji-Hye Song, Min-Sun Kim, Seung-Hyun Lee, Jin-Taek Hwang, Soo-Hyun Park, Sahng Wook Park, Sae-Bom Jeon, Ru-Ri Lee, Jangho Lee, and Hyo-Kyoung Choi
Elsevier BV
Sun-Ho Lee, Jangho Lee, Jaewon Oh, Jin-Taek Hwang, Hae-Jeung Lee, Hwa Kyung Byun, Hyeong-Jin Kim, David Suh, Ho-Geun Yoon, Sahng Wook Park,et al.
Oxford University Press (OUP)
Abstract Aims Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. Methods and results We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites—D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. Conclusion Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.
Sae-Bom Jeon, Hyoeun Kim, Kyeong-Hyeon Chun, Jaewon Oh, Chulan Kwon, Hyo-Kyoung Choi, Sangwoo Kim, Hyoung-Pyo Kim, In-Cheol Kim, Jung-Yoon Yoo,et al.
Elsevier BV
Hyoeun Kim, Hyeong-Jin Kim, Jaewon Oh, Seung-Tae Lee, Dongju Won, Hyo-Kyoung Choi, Jong Rak Choi, Sangwoo Kim, Hyoung-Pyo Kim, Seok-Jun Kim,et al.
Elsevier BV
Yun-Ji Cha, Sae-Bom Jeon, Jaewon Oh, Seung-Tae Lee, Sangwoo Kim, Hyoeun Kim, Jungyoon Choi, Hyo-Kyoung Choi, Dongju Won, Jong Rak Choi,et al.
Elsevier BV
Sun-Ho Lee, Jaewon Oh, Seung-Tae Lee, Dongju Won, Sangwoo Kim, Hyo-Kyoung Choi, Seok-Jun Kim, Hyunho Han, Minjae Yoon, Jong Rak Choi,et al.
Elsevier BV
Jaewon Oh, Sun-Ho Lee, Jungyoon Choi, Jong Rak Choi, Sangwoo Kim, Yun-Ji Cha, Hyo-Kyoung Choi, Dongju Won, Ho-Geun Yoon, Sahng Wook Park,et al.
Elsevier BV
Seon-Jin Yoon, Hye Young Son, Jin-Kyoung Shim, Ju Hyung Moon, Eui-Hyun Kim, Jong Hee Chang, Wan Yee Teo, Se Hoon Kim, Sahng Wook Park, Yong-Min Huh,et al.
Springer Science and Business Media LLC
Abstract Background Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. Methods We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. Results We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5. Conclusions GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.
Seon‐Jin Yoon, Juhwan Noh, Hye Young Son, Ju Hyung Moon, Eui‐Hyun Kim, Sahng Wook Park, Se Hoon Kim, Jong Hee Chang, Yong‐Min Huh, and Seok‐Gu Kang
Wiley
AbstractAn increasing number of studies indicate air pollutants infiltrate into the brain. We aimed to find the association of cumulative air pollution exposure in the main body of primary brain tumor: glioblastoma (GBM). In this double‐cohort, retrospective analysis study with a protocol, we compared the health effect of air pollution on the GBM patients from the SEER (Surveillance, Epidemiology, and End Results Program) in 27 U.S. counties from 10 states and GBM patients of Severance cohort of Korea. From 2000 to 2015, 10621 GBM patients of the SEER were individually evaluated for the cumulative average exposure for each pollutant, and 9444 (88.9%) mortality events were reported. From 2011 to 2018, 398 GBM patients of the Severance with the same protocol showed 259 (65.1%) mortality events. The multi‐pollutant models show that the association level of risk with CO is increased in the SEER (HR 1.252; 95% CI 1.141‐1.373) with an increasing linear trend of relative death rate in the spline curve. The Severance GBM data showed such a statistically significant result of the health impact of CO on GBM patients. The overall survival gain of the less exposure group against CO was 2 and 3 months in the two cohorts. Perioperative exposure to CO may increase the risk of shorter survival of GBM patients of the SEER and the Severance cohort.
Hyo-Jin Kim, Jangho Lee, Min-Yu Chung, Seungpyo Hong, Jae Ho Park, Seung-Hyun Lee, Sahng Wook Park, Hyo-Kyoung Choi, and Jin-Taek Hwang
Elsevier BV
Seon-Jin Yoon, Jungmin Park, Youngmin Shin, Yuna Choi, Sahng Wook Park, Seok-Gu Kang, Hye Young Son, and Yong-Min Huh
Springer Science and Business Media LLC
Abstract Background Gastric cancer is a considerable burden for worldwide patients. And diffuse gastric cancer is the most insidious subgroup with poor survival. The phenotypic characterization of the diffuse gastric cancer cell line can be useful for gastric cancer researchers. In this article, we aimed to characterize the diffuse gastric cancer cells with MRI and transcriptomic data. We hypothesized that gene expression pattern is associated with the phenotype of the cells and that the heterogeneous enhancement pattern and the high tumorigenicity of SNU484 can be modulated by the perturbation of the highly expressed gene. Methods We evaluated the 9.4 T magnetic resonance imaging and transcriptomic data of the orthotopic mice models from diffuse gastric cancer cells such as SNU484, Hs746T, SNU668, and KATO III. We included MKN74 as an intestinal cancer control cell. After comprehensive analysis integrating MRI and transcriptomic data, we selected CD34 and validated the effect by shRNA in the BALB/c nude mice models. Results SNU484, SNU668, Hs746T, and MKN74 formed orthotopic tumors by the 5 weeks after cell injection. The diffuse phenotype was found in the SNU484 and Hs746T. SNU484 was the only tumor showing the heterogeneous enhancement pattern on T2 images with a high level of CD34 expression. Knockdown of CD34 decreased the round-void shape in the H&E staining (P = 0.028), the heterogeneous T2 enhancement, and orthotopic tumorigenicity (100% vs 66.7%). The RNAseq showed that the suppressed CD34 is associated with the downregulated gene-sets of the extracellular matrix remodeling. Conclusion Suppression of CD34 in the human-originated gastric cancer cell suggests that it is important for the round-void histologic shape, heterogeneous enhancement pattern on MRI, and the growth of gastric cancer cell line.
Hyun-Duk Jang, Sang Eun Lee, Jimin Yang, Hyun-Chae Lee, Dasom Shin, Hwan Lee, Jaewon Lee, Sooryeonhwa Jin, Soungchan Kim, Seung Ji Lee,et al.
Oxford University Press (OUP)
Abstract Aims Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. Methods and results The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. Conclusion We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.
Kyoung-Mi Lee, Kwang Hwan Park, Ji Suk Hwang, Moses Lee, Dong Suk Yoon, Hyun Aae Ryu, Ho Sun Jung, Ki Won Park, Jihyun Kim, Sahng Wook Park,et al.
Springer Science and Business Media LLC
AbstractThe regulation of osteogenesis is important for bone formation and fracture healing. Despite advances in understanding the molecular mechanisms of osteogenesis, crucial modulators in this process are not well-characterized. Here we demonstrate that suppression of signal transducer and activator of transcription 5A (STAT5A) activates distal-less homeobox 5 (DLX5) in human bone marrow-derived stromal cells (hBMSCs) and enhances osteogenesis in vitro and in vivo. We show that STAT5A negatively regulates expression of Dlx5 in vitro and that STAT5A deletion results in increased trabecular and cortical bone mass and bone mineral density in mice. Additionally, STAT5A deletion prevents age-related bone loss. In a murine fracture model, STAT5A deletion was found to significantly enhance bone remodeling by stimulating the formation of a fracture callus. Our findings indicate that STAT5A inhibition enhances bone formation by promoting osteogenesis of BMSCs.
Hyo-Kyoung Choi, Jin-Taek Hwang, Tae-Gyu Nam, Sung Hee Kim, Dong-Kook Min, Sahng Wook Park, and Min-Yu Chung
Royal Society of Chemistry (RSC)
Statins mediate the transactivation of PCSK9, which in turn limits their cholesterol-lowering effects via LDL receptor (LDLR) degradation.
Dong-Kook Min, Hyun-Sook Lee, Narae Lee, Chan Joo Lee, Hyun Joo Song, Ga Eul Yang, Dojun Yoon, and Sahng Wook Park
Yonsei University College of Medicine
Purpose Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulation of the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR. Materials and Methods We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silico screening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo. Results A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependent manner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice. Conclusion Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.
Dan Heo, Chanjoo Lee, Minhee Ku, Seungjoo Haam, Jin-Suck Suh, Yong-Min Huh, Sahng Wook Park, and Jaemoon Yang
IOP Publishing
The specific delivery of ribonucleic acid (RNA) interfering molecules to disease-related cells is still a critical blockade for in vivo systemic treatment. Here, this study suggests a robust delivery carrier for targeted delivery of RNA-interfering molecules using galactosylated magnetic nanovectors (gMNVs). gMNVs are an organic–inorganic polymeric nanomaterial composed of polycationics and magnetic nanocrystal for delivery of RNA-interfering molecules and tracking via magnetic resonance (MR) imaging. In particular, the surface of gMNVs was modified by galactosylgluconic groups for targeted delivering to asialoglycoprotein receptor (ASGPR) of hepatocytes. Moreover, the small interfering RNAs were used to regulate target proteins related with low-density lipoprotein level and in vivo MR imaging was conducted for tracking of nanovectors. The obtained results show that the prepared gMNVs demonstrate potential as a systemic theragnostic nanoplatform for RNA interference and MR imaging.
H Choi, H Lee, T-H Kim, H J Kim, Y J Lee, S J Lee, J H Yu, D Kim, K-S Kim, S W Park,et al.
Springer Science and Business Media LLC
Seung-Hyun Yang, Dan Heo, Eugene Lee, Eunjung Kim, Eun-Kyung Lim, Young Han Lee, Seungjoo Haam, Jin-Suck Suh, Yong-Min Huh, Jaemoon Yang,et al.
IOP Publishing
Cancer cells can express specific biomarkers, such as cell membrane proteins and signaling factors. Thus, finding biomarkers and delivering diagnostic agents are important in the diagnosis of cancer. In this study, we investigated a biomarker imaging agent for the diagnosis of hepatic cancers. The asialoglycoprotein receptor (ASGPr) was selected as a biomarker for hepatoma cells and the ASGPr-targetable imaging agent bearing a galactosyl group was prepared using manganese ferrite nanoparticles (MFNP) and galactosylgluconic acid. The utility of the ASGPr-targetable imaging agent, galactosylated MFNP (G-MFNP) was assessed by several methods in ASGPr-expressing HepG2 cells as target cells and ASGPr-deficient MCF7 cells. Physical and chemical properties of G-MFNP were examined using Fourier-transform infrared spectroscopy, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. No significant cytotoxicity was observed in either cell line. Targeting ability was assessed using flow cytometry, magnetic resonance imaging, inductively coupled plasma atomic emission spectroscopy, absorbance analysis, dark-field microscopy, Prussian blue staining, and transmission electron microscopy. We demonstrated that G-MFNP target successfully and bind to ASGPr-expressing HepG2 cells specifically. We suggest that these results will be useful in strategies for cancer diagnoses based on magnetic resonance imaging.
Hee Eun Kim, Eunju Bae, Deok-yoon Jeong, Min-Ji Kim, Won-Ji Jin, Sahng-Wook Park, Gil-Soo Han, George M. Carman, Eunjin Koh, and Kyung-Sup Kim
Portland Press Ltd.
PPARγ (peroxisome-proliferator-activated receptor γ) is a master transcription factor involved in adipogenesis through regulating adipocyte-specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBPα (CCAAT/enhancer-binding protein α) and PPARγ network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPARγ is largely unknown. The results of the present study show that lipin1 activates PPARγ by releasing co-repressors, NCoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator of retinoid and thyroid hormone receptor), from PPARγ in the absence of the ligand rosiglitazone. We also identified a novel lipin1 TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPARγ, but not PPARα. Furthermore, this TAD is unique to lipin1 since this region does not show any homology with the other lipin isoforms, lipin2 and lipin3. The activity of the lipin1 TAD is enhanced by p300 and SRC-1 (steroid receptor co-activator 1), but not by PCAF (p300/CBP-associated factor) and PGC-1α (PPAR co-activator 1α). The physical interaction between lipin1 and PPARγ occurs at the lipin1 C-terminal region from residues 825 to 926, and the VXXLL motif at residue 885 is critical for binding with and the activation of PPARγ. The action of lipin1 as a co-activator of PPARγ enhanced adipocyte differentiation; the TAD and VXXLL motif played critical roles, but the catalytic activity of lipin1 was not directly involved. Collectively, these data suggest that lipin1 functions as a key regulator of PPARγ activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARα activation.
Chan Joo Lee, Yong-ho Lee, Sahng Wook Park, Kwang Joon Kim, Sungha Park, Jong-Chan Youn, Sang-Hak Lee, Seok-Min Kang, and Yangsoo Jang
Elsevier BV
Seung-Hyun Yang, Dan Heo, Jinsung Park, Sungsoo Na, Jin-Suck Suh, Seungjoo Haam, Sahng Wook Park, Yong-Min Huh, and Jaemoon Yang
IOP Publishing
Amphiphilic surfactants have been used to disperse magnetic nanoparticles in biological media, because they exhibit a dual hydrophobic/hydrophilic affinity that facilitates the formation of a nanoemulsion, within which nanoparticle surfaces can be modified to achieve different physicochemical properties. For the investigation of the interactions of cells with charged magnetic nanoparticles in a biological medium, we selected the nanoemulsion method to prepare water-soluble magnetic nanoparticles using amphiphilic surfactant (polysorbate 80). The hydroxyl groups of polysorbate 80 were modified to carboxyl or amine groups. The chemical structures of carboxylated and aminated polysorbate 80 were confirmed, and water-soluble manganese ferrite nanoparticles (MFNPs) were synthesized with three types of polysorbate 80. Colloidal size, morphology, monodispersity, solubility and T2 relaxivity were found to be similar between the three types of MFNP. However, cationic MFNPs exhibited greater cytotoxicity in macrophages (RAW264.7 cells) and lower cellular membrane effective stiffness than anionic and non-ionic MFNPs. Moreover, cationic MFNPs exhibited large uptake efficiency for RAW264.7 cells compared with anionic or non-ionic MFNPs under the same conditions. Therefore, we propose that surface charge should be a key consideration factor in the design of magnetic nanoparticles for theragnostic applications.
Jong-Seok Moon, Hee Eun Kim, Eunjin Koh, Se Ho Park, Won-Ji Jin, Byeong-Woo Park, Sahng Wook Park, and Kyung-Sup Kim
Elsevier BV
Krüppel-like factor 4 (KLF4) is a transcription factor that plays an important role in cell differentiation, proliferation, and survival, especially in the context of cancers. This study revealed that KLF4 activates glycolytic metabolism in breast cancer cells by up-regulating the platelet isoform of phosphofructokinase (PFKP). KLF4 activated the transcription of the PFKP gene by directly binding to the PFKP promoter. Whereas glucose uptake and lactate production were inhibited by the knockdown of KLF4, they were activated by the overexpression of KLF4. Unlike PFKP, the expressions of the other isoforms of phosphofructokinase and glycolytic genes were unaffected by KLF4. The human breast cancer tissues showed a close correlation between KLF4 and PFKP expression. This study also showed that PFKP plays a critical role in cell proliferation in breast cancer cells. In conclusion, it is suggested that KLF4 plays a role in maintenance of high glycolytic metabolism by transcriptional activation of the PFKP gene in breast cancer cells.
Jong-Seok Moon, Won-Ji Jin, Jin-Hye Kwak, Hyo-Jeong Kim, Mi-Jin Yun, Jae-Woo KIM, Sahng Wook Park, and Kyung-Sup Kim
Portland Press Ltd.
Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.
Bin Dong, Minhao Wu, Hai Li, Fredric B. Kraemer, Khosrow Adeli, Nabil G. Seidah, Sahng Wook Park, and Jingwen Liu
Elsevier BV
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.