High Free Cholesterol Bioavailability Drives the Tissue Pathologies in Scarb1
| Autor: | Antonio M. Gotto, Corina Rosales, Dedipya Yelamanchili, Jing Liu, Baiba K. Gillard, Henry J. Pownall |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty Cell Biological Availability Article Cell Line chemistry.chemical_compound Sex Factors Internal medicine Mole medicine Animals Humans Tissue Distribution Scavenger receptor Mice Knockout Cholesterol Macrophages Cholesterol HDL Wild type Cholesterol LDL Scavenger Receptors Class B Atherosclerosis SCARB1 Plaque Atherosclerotic Bioavailability Mice Inbred C57BL Kinetics Endocrinology medicine.anatomical_structure Phenotype chemistry Female Cardiology and Cardiovascular Medicine Lipoprotein |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 |
| Popis: | Objective: Overall and atherosclerosis-associated mortality is elevated in humans with very high HDL (high-density lipoprotein) cholesterol concentrations. Mice with a deficiency of the HDL receptor, Scarb1 (scavenger receptor class B type 1), are a robust model of this phenotype and exhibit several additional pathologies. We hypothesized that the previously reported high plasma concentration of free cholesterol (FC)–rich HDL in Scarb1 −/ − mice produces a state of high HDL-FC bioavailability that increases whole-body FC and dysfunction in multiple tissue sites. Approach and Results: The higher mol% FC in Scarb1 −/− versus WT (wild type) HDL (41.1 versus 16.0 mol%) affords greater FC bioavailability for transfer to multiple sites. Plasma clearance of autologous HDL-FC mass was faster in WT versus Scarb1 −/− mice. FC influx from Scarb1 −/− HDL to LDL (low-density lipoprotein) and J774 macrophages was greater (≈4×) than that from WT HDL, whereas FC efflux capacity was similar. The higher mol% FC of ovaries, erythrocytes, heart, and macrophages of Scarb1 −/− versus WT mice is associated with previously reported female infertility, impaired cell maturation, cardiac dysfunction, and atherosclerosis. The FC contents of other tissues were similar in the two genotypes, and these tissues were not associated with any overt pathology. In addition to the differences between WT versus Scarb1 −/− mice, there were many sex-dependent differences in tissue-lipid composition and plasma FC clearance rates. Conclusions: Higher HDL-FC bioavailability among Scarb1 −/− versus WT mice drives increased FC content of multiple cell sites and is a potential biomarker that is mechanistically linked to multiple pathologies. |
| Databáze: | OpenAIRE |
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