Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia
Open accessAbstract
Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr(-/-) mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4alpha or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4alpha, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for excretion into the feces. In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease.
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The reduction in HDL cholesterol with obeticholic acid may result from increased hepatic scavenger receptor B1 expression, which is up-regulated by FXR activation and stimulates hepatic uptake of cholesterol from HDL.
“This finding may result from increased hepatic scavenger receptor B1 expression, which is up-regulated by FXR activation and stimulates hepatic uptake of cholesterol from HDL. 32”
From A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis (2016) · cites this paper as [32]
The Discussion (page unavailable) says FXR activation increases hepatic SR-BI expression and lowers plasma HDL cholesterol through increased cholesterol clearance. The FXR-dependent Hypolipidemia section reports this effect in mice treated with GW4064, not obeticholic acid. The proposed mechanism is supported, but its application to the obeticholic-acid finding is an extrapolation. (LLM, conf=0.85)
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- Authors
- Zhang, Y., Yin, L., Anderson, J., Ma, H., Gonzalez, F. J., Willson, T. M., & Edwards, P. A.
- Affiliations
- Northeast Ohio Medical University (US)
- University of California, Los Angeles (US)
- National Institutes of Health (US)
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Zhang, Yanqiao
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 285
- Issue
- 5
- Pages
- 3035-3043
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2823426
- OpenAlex
- W2003716266
- Cited by
- 112
- References
- 52
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 12 · 2019: 8 · 2018: 2 · 2017: 8 · 2016: 7 · 2015: 1 · 2014: 11 · 2013: 8 · 2012: 10
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Massachusetts Institute of Technology
- National Institutes of Health (HL30568)
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (HL3 0568, HL 68445, P01HL030568, R01HL068445)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- farnesoid X receptor, hypocholesterolemia, scavenger receptor class B type I, HNF4α, JNK phosphorylation, reverse cholesterol transport, intestinal cholesterol absorption, hypercholesterolemia, coronary artery disease, bile acid homeostasis, FXR agonists, FXR knockout mice
- MeSH terms
- Absorption, Receptor, Farnesoid X-Activated, Animals, Cell Line, Cholesterol, Coronary Disease, Glucose, Homeostasis, Humans, Lipoproteins, Liver, Models, Biological, Receptors, Cytoplasmic and Nuclear, Scavenger Receptors, Class B, Mice, Hepatocyte Nuclear Factor 4
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