Respective contributions of intestinal Niemann-Pick C1-like 1 and scavenger receptor class B type I to cholesterol and tocopherol uptake: in vivov. in vitro studies

The intestinal absorption of cholesterol and lipid micronutrients such as vitamin E has been shown to share some common pathways. The present study aims to further compare the uptake of cholesterol ([3H]cholesterol v. 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3-ol (NBD-cholesterol)) and tocopherol in Caco-2 TC-7 cells and in mouse intestine, with special focus on the respective roles of scavenger receptor class B type I (SR-BI) and Niemann-Pick C1-like 1 (NPC1L1). Conversely to NBD-cholesterol, the uptakes of [3H]cholesterol and tocopherol by Caco-2 cells were impaired by both block lipid transport-1 and ezetimibe, which inhibit SR-BI and NPC1L1, respectively. These inhibitions occurred only when cholesterol or tocopherol was delivered to cells included in micelles that contained biliary acid and at least oleic acid as a lipid. In vivo, after 2 h of digestion in mice, the uptake of the two cholesterol analogues and of tocopherol all showed distinct patterns along the duodenum–jejunum axis. [3H]Cholesterol uptake, which correlated closely to NPC1L1 mRNA expression in wild-type (wt) mice, was strongly inhibited by ezetimibe. Intestinal SR-BI overexpression did not change NPC1L1 expression and led to a significant increase in [3H]cholesterol uptake in the distal jejunum. Conversely, neither ezetimibe treatment nor SR-BI overexpression had an effect on NBD-cholesterol uptake. However, in contrast with SR-BI mRNA expression, tocopherol absorption increased strongly up to the distal jejunum in wt mice where it was specifically inhibited by ezetimibe, and was increased in the proximal intestine of intestinal SR-BI-overexpressing mice. Thus, cholesterol and tocopherol uptakes share common pathways in cell culture models, but display different in vivo absorption patterns associated with distinct contributions of SR-BI and NPC1L1.

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A Human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo

Hepatology ◽

10.1002/hep.24692 ◽

2011 ◽

Vol 55 (2) ◽

pp. 364-372 ◽

Cited By ~ 97

Author(s):

Philip Meuleman ◽

Maria Teresa Catanese ◽

Lieven Verhoye ◽

Isabelle Desombere ◽

Ali Farhoudi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Human Monoclonal Antibody ◽

Scavenger Receptor ◽

Type I ◽

Hepatitis C Virus Infection ◽

Viral Spread ◽

Scavenger Receptor Class ◽

Class B

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p21-activated Kinase-1 (PAK1) Inhibition of the Human Scavenger Receptor Class B, Type I Promoter in Macrophages Is Independent of PAK1 Kinase Activity, but Requires the GTPase-binding Domain

Journal of Biological Chemistry ◽

10.1074/jbc.m103176200 ◽

2001 ◽

Vol 276 (50) ◽

pp. 46807-46814 ◽

Cited By ~ 12

Author(s):

Thomas G. Hullinger ◽

Robert L. Panek ◽

Xiangyang Xu ◽

Sotirios K. Karathanasis

Keyword(s):

High Density Lipoprotein ◽

Promoter Activity ◽

Kinase Activity ◽

Scavenger Receptor ◽

Density Lipoprotein ◽

Type I ◽

Down Regulation ◽

Scavenger Receptor Class ◽

Class B

Scavenger receptor class B, type I (SR-BI), is a high density lipoprotein receptor that mediates the flux of cholesterol between high density lipoprotein and cells. Recent evidence suggests that SR-BI plays a role in atherosclerosis and that inflammatory mediators down-regulate SR-BI in the macrophage. The purpose of this study was to evaluate the ability of lipopolysaccharide (LPS) to down-regulate the activity of the human SR-BI promoter in the macrophage and to delineate the mechanisms involved. Experiments with cultured cells andin vivoderived macrophages showed that LPS has a powerful suppressive effect on SR-BI expression bothin vitroandin vivo. Transient transfection studies demonstrated that LPS represses SR-BI promoter activity in the macrophage cell line RAW 264.7. Cotransfection with either a constitutively active p21-activated protein kinase-1 (PAK1) construct (T423E) or a kinase-deficient PAK1 construct (K299R) resulted in repression of the SR-BI promoter, similar to LPS. These results demonstrate that PAK1-mediated down-regulation of the SR-BI promoter is independent of PAK1 kinase activity and suggest that PAK1 mediates the LPS-induced decrease in promoter activity. Cotransfection with constitutively active Cdc42 or Rac expression constructs also resulted in down-regulation of the promoter; whereas the dominant-negative Cdc42 and Rac constructs elevated basal promoter activity and blunted the LPS response. Cotransfection of PAK1 constructs containing mutations in both the kinase domain and the Cdc42/Rac-binding domain attenuated the PAK1-mediated down-regulation of the promoter, suggesting that Rac and Cdc42 are required for PAK1-mediated decreases in SR-BI promoter activity. 5′-Deletion analysis and gel shift data suggest that LPS inhibits binding of a novel transcription factor to a myeloid zing finger protein-1-like element (−476 to −456) in the human SR-BI promoter. These results demonstrate that the PAK1 pathway down-regulates the SR-BI promoter and suggest that activation of this pathway may play an important role in cholesterol trafficking in the vessel wall.

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Probucol increases hepatic expression of High Density Lipoprotein (HDL) receptor, scavenger receptor class B type I (SR-BI), in vitro and in vivo. — enhancement of reverse cholesterol transport (RCT)

Atherosclerosis ◽

10.1016/s0021-9150(00)80417-7 ◽

2000 ◽

Vol 151 (1) ◽

pp. 92

Author(s):

K. Tsujii ◽

K. Hirano ◽

F. Matsuura ◽

Y. Nakagawa-Toyama ◽

T. Sugimoto ◽

...

Keyword(s):

Reverse Cholesterol Transport ◽

Scavenger Receptor ◽

Density Lipoprotein ◽

Cholesterol Transport ◽

Type I ◽

Hepatic Expression ◽

Scavenger Receptor Class ◽

Class B

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Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo

Journal of Clinical Investigation ◽

10.1172/jci25327 ◽

2005 ◽

Vol 115 (10) ◽

pp. 2870-2874 ◽

Cited By ~ 227

Author(s):

Y. Zhang

Keyword(s):

Reverse Cholesterol Transport ◽

Scavenger Receptor ◽

Cholesterol Transport ◽

Type I ◽

Hepatic Expression ◽

Positive Regulator ◽

Scavenger Receptor Class ◽

Class B

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Scavenger Receptor Class B Type I and Hepatitis C Virus Infection of Primary Tupaia Hepatocytes

Journal of Virology ◽

10.1128/jvi.79.9.5774-5785.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5774-5785 ◽

Cited By ~ 65

Author(s):

Heidi Barth ◽

Raffaele Cerino ◽

Mirko Arcuri ◽

Marco Hoffmann ◽

Peter Schürmann ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Surface ◽

Scavenger Receptor ◽

Hcv Infection ◽

Type I ◽

Scavenger Receptor Class ◽

Class B

ABSTRACT Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. The study of early steps during HCV infection has been hampered by the lack of suitable in vitro or in vivo models. Primary Tupaia hepatocytes (PTH) have been shown to be susceptible to HCV infection in vitro and in vivo. Human scavenger receptor class B type I (SR-BI) represents an HCV receptor candidate mediating the cellular binding of E2 glycoprotein to HepG2 hepatoma cells. However, the function of SR-BI for viral infection of hepatocytes is unknown. In this study, we used PTH to assess the functional role of SR-BI as a putative HCV receptor. Sequence analysis of cloned tupaia SR-BI revealed a high homology between tupaia and human SR-BI. Transfection of CHO cells with human or tupaia SR-BI but not mouse SR-BI cDNA resulted in cellular E2 binding, suggesting that E2-binding domains between human and tupaia SR-BI are highly conserved. Preincubation of PTH with anti-SR-BI antibodies resulted in marked inhibition of E2 or HCV-like particle binding. However, anti-SR-BI antibodies were not able to block HCV infection of PTH. In conclusion, our results demonstrate that SR-BI represents an important cell surface molecule for the binding of the HCV envelope to hepatocytes and suggest that other or additional cell surface molecules are required for the initiation of HCV infection. Furthermore, the structural and functional similarities between human and tupaia SR-BI indicate that PTH represent a useful model system to characterize the molecular interaction of the HCV envelope and SR-BI on primary hepatocytes.

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Scavenger receptor class B type I in high-density lipoprotein metabolism, atherosclerosis and heart disease: lessons from gene-targeted mice

Biochemical Society Transactions ◽

10.1042/bst0320116 ◽

2004 ◽

Vol 32 (1) ◽

pp. 116-120 ◽

Cited By ~ 25

Author(s):

B. Trigatti ◽

S. Covey ◽

A. Rizvi

Keyword(s):

Bone Marrow ◽

Heart Disease ◽

Knockout Mice ◽

Scavenger Receptor ◽

Density Lipoprotein ◽

Type I ◽

Scavenger Receptor Class ◽

Class B

The scavenger receptor class B type I (SR-BI) is a multi-ligand receptor that can mediate the binding and bi-directional lipid transfer between high-density lipoproteins (HDLs) and cells. It is expressed in a variety of tissues, including the liver, and in macrophages in atherosclerotic plaques. The physiological role of SR-BI has been tested in vivo by the genetic manipulation of SR-BI levels in mice. Mice lacking SR-BI exhibit impaired hepatic-selective HDL cholesterol uptake and increased atherosclerosis, suggesting that SR-BI is required for hepatic reverse cholesterol transport and normally protects against atherosclerosis. Surprisingly, elimination of SR-BI in apolipoprotein E knockout mice results in rapid development of occlusive coronary artery disease, accompanied by spontaneous myocardial infarction, reduced heart function and early death, which points to a role for SR-BI in protection against coronary heart disease. The in vivo role of macrophage SR-BI has been less clear. We have used bone-marrow transplantation to demonstrate that bone-marrow-derived SR-BI also normally protects against atherosclerosis in low-density lipoprotein receptor knockout mice. These results suggest that SR-BI may have multiple protective effects against atherosclerosis in different tissues.

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