Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues

Huby, T.; Doucet, C.; Dachet, C.; Ouzilleau, B.; Ueda, Y.; Afzal, V.; Rubin, E.; Chapman, M. J.; Lesnik, P.

doi:10.1172/jci26893

Cited by 124Cholesterol and Lipid MetabolismAtherosclerosis and Cardiovascular DiseasesLipoproteins and Cardiovascular Health

Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues

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Huby, T., Doucet, C., Dachet, C., Ouzilleau, B., Ueda, Y., Afzal, V., Rubin, E., Chapman, M. J. +1 more·2006·Journal of Clinical Investigation

DOI 10.1172/jci26893

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Abstract

Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BI gene inactivation of the hypomorphic SR-BI allele in hepatocytes (hypomSR-BI-KO(liver)) was associated with high plasma TC concentrations, increased plasma free cholesterol/TC (FC/TC) ratio, and a lipoprotein-cholesterol profile typical of SR-BI-/- mice. Plasma TC levels were increased 2-fold in hypomSR-BI and control mice fed an atherogenic diet, whereas hypomSR-BI-KO(liver) and SR-BI-/- mice developed severe hypercholesterolemia due to accumulation of FC-rich, VLDL-sized particles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold) compared with that in controls, but to a much lower degree than in hypomSR-BI-KO(liver) (32-fold) and SR-BI-/- (48-fold) mice. The latter models did not differ in either plasma lipid levels or in the capacity of VLDL-sized lipoproteins to induce macrophage cholesterol loading. However, reduced atherosclerosis in hypomSR-BI-KO(liver) mice was associated with decreased lesional macrophage content as compared with that in SR-BI-/- mice. These data imply that, in addition to its major atheroprotective role in liver, SR-BI may exert an antiatherogenic role in extrahepatic tissues.

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Lack of SR-BI increases HDL-C but is atherogenic.
“On the other hand, lack of SR-BI increases HDL-C, but is atherogenic [42].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [42]

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Decreased Atherosclerosis in Heterozygous Low Density Lipoprotein Receptor-deficient Mice Expressing the Scavenger Receptor BI Transgene
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Scavenger receptor class B type I in high-density lipoprotein metabolism, atherosclerosis and heart disease: lessons from gene-targeted mice
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Gene Transfer and Hepatic Overexpression of the HDL Receptor SR-BI Reduces Atherosclerosis in the Cholesterol-Fed LDL Receptor–Deficient Mouse
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The Role of Macrophage Scavenger Receptor Class B, Type 1 (SR-BI) in the development of Atheroscelerosis in Apolipoprotein E Deficient Mice
Risvi, A. A. (2003) · MacSphere (McMaster University) · doi:10.71548/5585
Macrophage SR-BI and Atherosclerosis
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Authors: Huby, T., Doucet, C., Dachet, C., Ouzilleau, B., Ueda, Y., Afzal, V., Rubin, E., Chapman, M. J., & Lesnik, P.
Affiliations: Inserm (FR)
Kyoto University (JP)
Lawrence Berkeley National Laboratory (US)
Corresponding author: Huby, T.
ORCID: Huby, T.
Afzal, V.
Rubin, E.
Chapman, M. J.
Lesnik, P.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2006-10-02
Volume: 116
Issue: 10
Pages: 2767-2776
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci26893
OpenAlex: W2041324378
Cited by: 124
References: 48
Citations by year: 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 8 · 2018: 8 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 11 · 2013: 3 · 2012: 7
FWCI: 8.13
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Funders: Pfizer
Institut National de la Santé et de la Recherche Médicale
Assistance Publique - Hôpitaux de Paris
Topics: Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords: scavenger receptor class B type I, atherosclerosis, hypercholesterolemia, HDL cholesterol, conditional knockout mice, free cholesterol, VLDL, atherogenic diet, serum cholesterol
MeSH terms: ATP Binding Cassette Transporter, Subfamily G, Member 1, CD68 Molecule, Alleles, Animals, Apolipoproteins, Cholesterol, Diet, Atherogenic, Female, Lipoproteins, Cholesterol, HDL, Cholesterol, LDL, Liver, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Sex Factors, Triglycerides, Antigens, Differentiation, Myelomonocytic, Cholesterol, VLDL, Antigens, CD, Interleukin-6, Gene Expression, Mice, Knockout, ATP-Binding Cassette Transporters, Atherosclerosis, Scavenger Receptors, Class B, Mice

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Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues

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