Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis
Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinas...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-05-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396416301372 |
| _version_ | 1818544545057472512 |
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| author | Yinyuan Ding Xunde Xian William L. Holland Shirling Tsai Joachim Herz |
| author_facet | Yinyuan Ding Xunde Xian William L. Holland Shirling Tsai Joachim Herz |
| author_sort | Yinyuan Ding |
| collection | DOAJ |
| description | Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion. |
| first_indexed | 2024-12-11T22:49:53Z |
| format | Article |
| id | doaj.art-479c937ece374119b250ab5162274dfc |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-11T22:49:53Z |
| publishDate | 2016-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-479c937ece374119b250ab5162274dfc2022-12-22T00:47:29ZengElsevierEBioMedicine2352-39642016-05-017C13514510.1016/j.ebiom.2016.04.002Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic SteatosisYinyuan Ding0Xunde Xian1William L. Holland2Shirling Tsai3Joachim Herz4Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USADepartment of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USALow-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL) triglyceride secretion.http://www.sciencedirect.com/science/article/pii/S2352396416301372Insulin, metabolic syndromeInsulin resistanceLRP1Chylomicron remnantDiabetesLipoproteinPDGF |
| spellingShingle | Yinyuan Ding Xunde Xian William L. Holland Shirling Tsai Joachim Herz Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis EBioMedicine Insulin, metabolic syndrome Insulin resistance LRP1 Chylomicron remnant Diabetes Lipoprotein PDGF |
| title | Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis |
| title_full | Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis |
| title_fullStr | Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis |
| title_full_unstemmed | Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis |
| title_short | Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis |
| title_sort | low density lipoprotein receptor related protein 1 protects against hepatic insulin resistance and hepatic steatosis |
| topic | Insulin, metabolic syndrome Insulin resistance LRP1 Chylomicron remnant Diabetes Lipoprotein PDGF |
| url | http://www.sciencedirect.com/science/article/pii/S2352396416301372 |
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