Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice
Summary: Cellular cholesterol is regulated by at least two transcriptional mechanisms involving sterol-regulatory-element-binding proteins (SREBPs) and liver X receptors (LXRs). Although SREBP and LXR pathways are the predominant mechanisms that sense cholesterol in the endoplasmic reticulum and nuc...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221010579 |
| _version_ | 1819129569786986496 |
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| author | George D. Dalton Seh-Hoon Oh Linda Tang Stephanie Zhang Amanda L. Brown Venkateshwari Varadharajan Camelia Baleanu-Gogonea Valentin Gogonea Preeti Pathak J. Mark Brown Anna Mae Diehl |
| author_facet | George D. Dalton Seh-Hoon Oh Linda Tang Stephanie Zhang Amanda L. Brown Venkateshwari Varadharajan Camelia Baleanu-Gogonea Valentin Gogonea Preeti Pathak J. Mark Brown Anna Mae Diehl |
| author_sort | George D. Dalton |
| collection | DOAJ |
| description | Summary: Cellular cholesterol is regulated by at least two transcriptional mechanisms involving sterol-regulatory-element-binding proteins (SREBPs) and liver X receptors (LXRs). Although SREBP and LXR pathways are the predominant mechanisms that sense cholesterol in the endoplasmic reticulum and nucleus to alter sterol-regulated gene expression, evidence suggests cholesterol in plasma membrane can be sensed by proteins in the Hedgehog (Hh) pathway which regulate organ self-renewal and are a morphogenic driver during embryonic development. Cholesterol interacts with the G-protein-coupled receptor Smoothened (Smo), which impacts downstream Hh signaling. Although evidence suggests cholesterol influences Hh signaling, it is not known whether Smo-dependent sterol sensing impacts cholesterol homeostasis in vivo. We examined dietary-cholesterol-induced reorganization of whole-body sterol and bile acid (BA) homeostasis in adult mice with inducible hepatocyte-specific Smo deletion. These studies demonstrate Smo in hepatocytes plays a regulatory role in sensing and feedback regulation of cholesterol balance driven by excess dietary cholesterol. |
| first_indexed | 2024-12-22T08:45:48Z |
| format | Article |
| id | doaj.art-bb55d9b8b9d44c2c84e49520c90d1dcf |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-22T08:45:48Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-bb55d9b8b9d44c2c84e49520c90d1dcf2022-12-21T18:32:08ZengElsevieriScience2589-00422021-09-01249103089Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in miceGeorge D. Dalton0Seh-Hoon Oh1Linda Tang2Stephanie Zhang3Amanda L. Brown4Venkateshwari Varadharajan5Camelia Baleanu-Gogonea6Valentin Gogonea7Preeti Pathak8J. Mark Brown9Anna Mae Diehl10Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USADivision of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USADivision of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USADivision of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Chemistry, Cleveland State University, Cleveland, OH 44115, USADepartment of Chemistry, Cleveland State University, Cleveland, OH 44115, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USADivision of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USA; Corresponding authorSummary: Cellular cholesterol is regulated by at least two transcriptional mechanisms involving sterol-regulatory-element-binding proteins (SREBPs) and liver X receptors (LXRs). Although SREBP and LXR pathways are the predominant mechanisms that sense cholesterol in the endoplasmic reticulum and nucleus to alter sterol-regulated gene expression, evidence suggests cholesterol in plasma membrane can be sensed by proteins in the Hedgehog (Hh) pathway which regulate organ self-renewal and are a morphogenic driver during embryonic development. Cholesterol interacts with the G-protein-coupled receptor Smoothened (Smo), which impacts downstream Hh signaling. Although evidence suggests cholesterol influences Hh signaling, it is not known whether Smo-dependent sterol sensing impacts cholesterol homeostasis in vivo. We examined dietary-cholesterol-induced reorganization of whole-body sterol and bile acid (BA) homeostasis in adult mice with inducible hepatocyte-specific Smo deletion. These studies demonstrate Smo in hepatocytes plays a regulatory role in sensing and feedback regulation of cholesterol balance driven by excess dietary cholesterol.http://www.sciencedirect.com/science/article/pii/S2589004221010579LipidMolecular physiologyMolecular biology |
| spellingShingle | George D. Dalton Seh-Hoon Oh Linda Tang Stephanie Zhang Amanda L. Brown Venkateshwari Varadharajan Camelia Baleanu-Gogonea Valentin Gogonea Preeti Pathak J. Mark Brown Anna Mae Diehl Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice iScience Lipid Molecular physiology Molecular biology |
| title | Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice |
| title_full | Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice |
| title_fullStr | Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice |
| title_full_unstemmed | Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice |
| title_short | Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice |
| title_sort | hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice |
| topic | Lipid Molecular physiology Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004221010579 |
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