title: Identification and characterization of NPC1L1 variants in Uygur and Kazakh with extreme low-density lipoprotein cholesterol.
abstract: BACKGROUND
  Plasma levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease and are influenced by both heredity and dietary habits. The Niemann-Pick C1 like 1 (NPC1L1) protein mediates efficient dietary cholesterol absorption and contributes to variations in human LDL-C levels.
  
  
  METHODS
  In the present study, using high throughput sequencing we identified three non-synonymous (NS) variations and 64 synonymous variations in the NPC1L1 gene from subsets of Chinese Han, Uygur and Kazakh populations with high or low LDL-C. Subsequently, three NS variations encoding R174H, V177I and V1284L substitutions were observed only in Uygur and Kazakh individuals with limited maximal plasma LDL-C levels.
  
  
  RESULTS
  In further experiments, we investigated cholesterol-regulated recycling and glycosylation and stability of these NS NPC1L1 variants. However, no significant differences between WT and variant NPC1L1 proteins were observed using in vivo assays in mouse livers with adenovirus-mediated expression, demonstrating that none of the three NPC1L1 NS variants caused decreased uptake of biliary cholesterol.
  
  
  CONCLUSIONS
  Simultaneously, these data indicate that R174H, V177I and V1284L NPC1L1 variations in high or low LDL-C individuals may not directly influence cholesterol absorption by NPC1L1.
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China; Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, China. Electronic address: yuanqinghua2005@sina.com.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China; Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, China. Electronic address: fuzhenyan316@126.com.
authors.forename: Zhenyan
authors.initials: Z
authors.lastname: Fu
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: weijian@sibs.ac.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Wei
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: lipeishan@sibs.ac.cn.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: hhmiao@sibcb.ac.cn.
authors.forename: Hong-Hua
authors.initials: HH
authors.lastname: Miao
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: yxqu@sibs.ac.cn.
authors.forename: Yu-Xiu
authors.initials: YX
authors.lastname: Qu
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: joyxusss@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: qjayadam@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: blli@sibcb.ac.cn.
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; The College of Life Sciences, Wuhan University, Wuhan, 430072, China. Electronic address: blsong@whu.edu.cn.
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Song
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China; Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, China. Electronic address: myt-xj@163.com.
authors.forename: Yitong
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002681:China / Q000208:ethnology; D015243:Cholesterol, VLDL / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics*; D065628:Intestinal Reabsorption / Q000235:genetics; D007623:Kazakhstan / Q000208:ethnology; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008813:Mice, Inbred ICR; D008875:Middle Aged; D016366:Open Reading Frames / Q000235:genetics; D051381:Rats
chemical_list: D015243:Cholesterol, VLDL; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human
keywords: Cholesterol absorption; Low-density lipoprotein cholesterol; NPC1L1; Variants