Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis
Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 i...
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| Veröffentlicht in: | The Journal of biological chemistry 2004-08, Vol.279 (32), p.33586-33592 |
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| container_title | The Journal of biological chemistry |
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| creator | Davis, Harry R. Zhu, Li-ji Hoos, Lizbeth M. Tetzloff, Glen Maguire, Maureen Liu, Jianjun Yao, Xiaorui Iyer, Sai Prasad N. Lam, My-Hanh Lund, Erik G. Detmers, Patricia A. Graziano, Michael P. Altmann, Scott W. |
| description | Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia. |
| doi_str_mv | 10.1074/jbc.M405817200 |
| format | Article |
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The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M405817200</identifier><identifier>PMID: 15173162</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Biological Transport ; Cholesterol - analysis ; Cholesterol - biosynthesis ; Cholesterol - metabolism ; Cholesterol, Dietary - administration & dosage ; Homeostasis - physiology ; Hypercholesterolemia - etiology ; Hypercholesterolemia - therapy ; Intestinal Absorption - physiology ; Intestinal Mucosa - metabolism ; Lipoproteins - blood ; Liver - chemistry ; Membrane Transport Proteins - genetics ; Membrane Transport Proteins - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phytosterols - blood ; Phytosterols - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - analysis ; Sitosterols - metabolism ; Triglycerides - metabolism</subject><ispartof>The Journal of biological chemistry, 2004-08, Vol.279 (32), p.33586-33592</ispartof><rights>2004 © 2004 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c506t-7fa3fef9eed66d52f1c8792d47300af7c37c9fe705e3d16eb28cbcfd2be362173</citedby><cites>FETCH-LOGICAL-c506t-7fa3fef9eed66d52f1c8792d47300af7c37c9fe705e3d16eb28cbcfd2be362173</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15173162$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Davis, Harry R.</creatorcontrib><creatorcontrib>Zhu, Li-ji</creatorcontrib><creatorcontrib>Hoos, Lizbeth M.</creatorcontrib><creatorcontrib>Tetzloff, Glen</creatorcontrib><creatorcontrib>Maguire, Maureen</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><creatorcontrib>Yao, Xiaorui</creatorcontrib><creatorcontrib>Iyer, Sai Prasad N.</creatorcontrib><creatorcontrib>Lam, My-Hanh</creatorcontrib><creatorcontrib>Lund, Erik G.</creatorcontrib><creatorcontrib>Detmers, Patricia A.</creatorcontrib><creatorcontrib>Graziano, Michael P.</creatorcontrib><creatorcontrib>Altmann, Scott W.</creatorcontrib><title>Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.</description><subject>Animals</subject><subject>Biological Transport</subject><subject>Cholesterol - analysis</subject><subject>Cholesterol - biosynthesis</subject><subject>Cholesterol - metabolism</subject><subject>Cholesterol, Dietary - administration & dosage</subject><subject>Homeostasis - physiology</subject><subject>Hypercholesterolemia - etiology</subject><subject>Hypercholesterolemia - therapy</subject><subject>Intestinal Absorption - physiology</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Lipoproteins - blood</subject><subject>Liver - chemistry</subject><subject>Membrane Transport Proteins - genetics</subject><subject>Membrane Transport Proteins - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Phytosterols - blood</subject><subject>Phytosterols - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - analysis</subject><subject>Sitosterols - metabolism</subject><subject>Triglycerides - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUGP0zAQhS0EYsvClSPyASE4pHjsJk6OKAK2orv0sAhulmOPiXeTuNgpqL-DP4yXVlpxwBdrNN97Gr1HyHNgS2By9famM8vLFStrkJyxB2QBrBaFKOHbQ7JgjEPR8LI-I09SumH5rRp4TM6gBCmg4gvy-8rjqKep2HpzS1ugG3-LFOjrq20LG3hD14nOPdL1NGOa_aQHuu0Pc0gzxjBQPVna9mHA03wd9ZR2Iebp707TT3igl8HuBz2HSIOjX-_wogv28I_yIoyYXXXy6Sl55PSQ8NnpPydfPry_bi-KzeeP6_bdpjAlq-ZCOi0cugbRVpUtuQNTy4bblRSMaSeNkKZxKFmJwkKFHa9NZ5zlHYqK5wDOyauj7y6GH_t8iBp9MjgMesKwTwpqBrIRIoPLI2hiSCmiU7voRx0PCpi6q0HlGtR9DVnw4uS870a09_gp9wy8PAK9_97_8hFV54PpcVRcNkpwJURZVxmrjxjmGH56jCoZj5NBmyVmVjb4_53wB8YFowY</recordid><startdate>20040806</startdate><enddate>20040806</enddate><creator>Davis, Harry R.</creator><creator>Zhu, Li-ji</creator><creator>Hoos, Lizbeth M.</creator><creator>Tetzloff, Glen</creator><creator>Maguire, Maureen</creator><creator>Liu, Jianjun</creator><creator>Yao, Xiaorui</creator><creator>Iyer, Sai Prasad N.</creator><creator>Lam, My-Hanh</creator><creator>Lund, Erik G.</creator><creator>Detmers, Patricia A.</creator><creator>Graziano, Michael P.</creator><creator>Altmann, Scott W.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20040806</creationdate><title>Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis</title><author>Davis, Harry R. ; Zhu, Li-ji ; Hoos, Lizbeth M. ; Tetzloff, Glen ; Maguire, Maureen ; Liu, Jianjun ; Yao, Xiaorui ; Iyer, Sai Prasad N. ; Lam, My-Hanh ; Lund, Erik G. ; Detmers, Patricia A. ; Graziano, Michael P. ; Altmann, Scott W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-7fa3fef9eed66d52f1c8792d47300af7c37c9fe705e3d16eb28cbcfd2be362173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Biological Transport</topic><topic>Cholesterol - analysis</topic><topic>Cholesterol - biosynthesis</topic><topic>Cholesterol - metabolism</topic><topic>Cholesterol, Dietary - administration & dosage</topic><topic>Homeostasis - physiology</topic><topic>Hypercholesterolemia - etiology</topic><topic>Hypercholesterolemia - therapy</topic><topic>Intestinal Absorption - physiology</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Lipoproteins - blood</topic><topic>Liver - chemistry</topic><topic>Membrane Transport Proteins - genetics</topic><topic>Membrane Transport Proteins - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Phytosterols - blood</topic><topic>Phytosterols - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - analysis</topic><topic>Sitosterols - metabolism</topic><topic>Triglycerides - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Davis, Harry R.</creatorcontrib><creatorcontrib>Zhu, Li-ji</creatorcontrib><creatorcontrib>Hoos, Lizbeth M.</creatorcontrib><creatorcontrib>Tetzloff, Glen</creatorcontrib><creatorcontrib>Maguire, Maureen</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><creatorcontrib>Yao, Xiaorui</creatorcontrib><creatorcontrib>Iyer, Sai Prasad N.</creatorcontrib><creatorcontrib>Lam, My-Hanh</creatorcontrib><creatorcontrib>Lund, Erik G.</creatorcontrib><creatorcontrib>Detmers, Patricia A.</creatorcontrib><creatorcontrib>Graziano, Michael P.</creatorcontrib><creatorcontrib>Altmann, Scott W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Davis, Harry R.</au><au>Zhu, Li-ji</au><au>Hoos, Lizbeth M.</au><au>Tetzloff, Glen</au><au>Maguire, Maureen</au><au>Liu, Jianjun</au><au>Yao, Xiaorui</au><au>Iyer, Sai Prasad N.</au><au>Lam, My-Hanh</au><au>Lund, Erik G.</au><au>Detmers, Patricia A.</au><au>Graziano, Michael P.</au><au>Altmann, Scott W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-08-06</date><risdate>2004</risdate><volume>279</volume><issue>32</issue><spage>33586</spage><epage>33592</epage><pages>33586-33592</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15173162</pmid><doi>10.1074/jbc.M405817200</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Transport Cholesterol - analysis Cholesterol - biosynthesis Cholesterol - metabolism Cholesterol, Dietary - administration & dosage Homeostasis - physiology Hypercholesterolemia - etiology Hypercholesterolemia - therapy Intestinal Absorption - physiology Intestinal Mucosa - metabolism Lipoproteins - blood Liver - chemistry Membrane Transport Proteins - genetics Membrane Transport Proteins - physiology Mice Mice, Inbred C57BL Mice, Knockout Phytosterols - blood Phytosterols - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - analysis Sitosterols - metabolism Triglycerides - metabolism |
| title | Niemann-Pick C1 Like 1 (NPC1L1) Is the Intestinal Phytosterol and Cholesterol Transporter and a Key Modulator of Whole-body Cholesterol Homeostasis |
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