Silencing of Mouse Hepatic Lanosterol 14-α Demethylase Down-Regulated Plasma Low-Density Lipoprotein Cholesterol Levels by Short-Term Treatment of siRNA(Pharmacognosy)
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概要
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Cytochrome P450 lanosterol 14-α demethylase (CYP51), participated in keeping serum cholesterol homeostasis, is a key enzyme to synthesize cholesterol from lanosterol. Here we focused on investigating the mechanism of CYP51 in modulating serum cholesterol levels in mouse through RNA interference (RNAi). Mice fed on normal or high fat high cholesterol (HFHC) diets were individually treated with small interference RNA (siRNA) of CYP51 gene by tail vein injection. The results showed that administrated single dose of 10 μg CYP51-siRNAs for 48 h resulted in significantly depletion of CYP51 mRNA in liver of mice fed on normal diet (from 40 to 60%, p<0.05). CYP51-siRNAs exerted the inhibition in a dose dependent manner (from 26% in 5 μg to 40% in 20 μg, p<0.05) and most inhibitive effect from day 3 to day 6 (over 50%,p<0.05) after the treatment. Six days after administration of 30 μg CYP51-siRNAs (20 μg on day 0 and 10 μg on day 3), CYP51 mRNA (normal: 50%; HFHC: 70%, p<0.05) and protein levels (normal and HFHC: over 40%,p<0.05) were significantly knocked down in mice liver. Interestingly, low-density lipoprotein receptor (LDLR) expression was significantly elevated compared with controls in hepatic cells after CYP51-siRNAs (mRNA: about 2 times; protein: about 1.6 times,p<0.05). As a consequence, about 50% of sera low-density lipoprotein cholesterol (LDL-ch) were significantly reduced (p<0.05). The effect on LDLR increase and LDL-ch reduction lasted 8 d after a single 20 μg CYP51-siRNAs injection. In addition, CYP51-siRNAs could not cause any fatty liver compared with Buffer-group and did not interfere with mice ovulation. In conclusion, these data demonstrated that CYP51-siRNAs silenced CYP51 in mouse liver and down-regulated plasma LDL-ch levels. The potential mechanism of LDL-ch reduction may be related to up-regulated LDLR expression of hepatic cells. It indicated that there was a cholesterol levels link-modulation system between cholesterol synthetic pathway through CYP51 and cholesterol transport pathway through LDLR in vivo.
- 公益社団法人日本薬学会の論文
- 2008-06-01
著者
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ZHANG Cheng
State Key Laboratory of Networking and Switching Technology, Beijing University of Posts and Telecom
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Yang Jie
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Zhang Cheng
State Key Laboratory Of Coal Combustion Huazhong University Of Science And Technology
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Xia Guoliang
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Liu Dan
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Liu Dan
State Key Lab For Mesoscopic Physics School Of Physics Peking University
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Zhou Bo
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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XU Baoshan
State Key Laboratories for AgroBiotechnology and Department of Animal Physiology and Biochemistry, C
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WANG Chao
State Key Laboratories for AgroBiotechnology and Department of Animal Physiology and Biochemistry, C
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MAO Guanping
State Key Laboratories for AgroBiotechnology and Department of Animal Physiology and Biochemistry, C
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TAI Ping
State Key Laboratories for AgroBiotechnology and Department of Animal Physiology and Biochemistry, C
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ZHANG Meijia
State Key Laboratories for AgroBiotechnology and Department of Animal Physiology and Biochemistry, C
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Tai Ping
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Xu Baoshan
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Mao Guanping
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Zhang Meijia
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Zhang Cheng
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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Wang Chao
State Key Laboratories For Agrobiotechnology And Department Of Animal Physiology And Biochemistry Co
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