Qinghua Yuan1, Zhenyan Fu2, Jian Wei3, Pei-Shan Li4, Hong-Hua Miao5, Yu-Xiu Qu6, Jie Xu7, Jie Qin8, Bo-Liang Li9, Bao-Liang Song10, Yitong Ma11. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. 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. 10. 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. 11. 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.
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.
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 V1284LNPC1L1 variations in high or low LDL-C individuals may not directly influence cholesterol absorption by NPC1L1.