Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease
Open accessAbstract
Background & aims Liver X receptors (LXRs) are lipid-activated nuclear receptors with important roles in cholesterol transport, lipogenesis, and anti-inflammatory signaling. Hepatic stellate cells activate during chronic liver injury and mediate the fibrotic response. These cells are also major repositories for lipids, but the role of lipid metabolism during stellate cell activation remains unclear. We investigated the role of LXR signaling stellate cell activation and susceptibility to fibrotic liver disease.Methods Immortalized and primary stellate cells purified from mice were treated with highly specific LXR ligands. Carbon tetrachloride and methionine/choline deficiency were used as chronic liver injury models. Reciprocal bone marrow transplants were performed to test the importance of hematopoietically derived cells to the fibrotic response.Results LXR ligands suppressed markers of fibrosis and stellate cell activation in primary mouse stellate cells. Lxrαβ(-/-) stellate cells produce increased levels of inflammatory mediators, and conditioned media from Lxrαβ(-/-) cells increases the fibrogenic program of wild-type cells. Furthermore, Lxrαβ(-/-) stellate cells exhibit altered lipid morphology and increased expression of fibrogenic genes, suggesting they are primed for activation. In vivo, Lxrαβ(-/-) mice have marked susceptibility to fibrosis in 2 injury models. Bone marrow transplants point to altered stellate cell function, rather than hematopoietic cell inflammation, as the primary basis for the Lxrαβ(-/-) phenotype.Conclusions These results reveal an unexpected role for LXR signaling and lipid metabolism in the modulation of hepatic stellate cell function.
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Exposure of LXR-/- animals to CCl4 or methionine choline deficiency diet leads to increased αSma and collagen proportionate area, respectively.
“exposition of LXR -/-animals to CCl 4 or methionine choline deficiency diet led to increased αSma and collagen proportionate area, respectively.”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [158]
Stimulation of LXR in wildtype HSCs results in decreased CCL-2 and IL-6 and suppression of col1α1 and Acta gene expression.
“Subsequently, the stimulation of LXR in wildtype HSCs resulted in decreased expression levels of CCL-2 and IL-6 next to a suppression of col1α1 and Acta gene expression.”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [158]
LXR-/- primary isolated HSCs show increased col1α1 and other pro-inflammatory gene expression compared to wildtype animals.
“LXR -/-primary isolated HSCs showed increased col1α1 and other pro-inflammatory gene expression (e.g., PDGF-β, Acta2 and CCL-2) compared to wildtype animals.”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [158]
LXR-β plays a pivotal role in liver fibrosis and HSC activation.
“Data presented by Beaven et al. highlighted the pivotal role of LXR-β in liver fibrosis and HSC activation.[158].”
From Nuclear receptors in liver fibrosis (2021) · cites this paper as [158]
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- Authors
- Beaven, S. W., Wroblewski, K., Wang, J., Hong, C., Bensinger, S., Tsukamoto, H., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Southern California (US)
- University of California, Los Angeles (US)
- Corresponding author
- Tontonoz, Peter
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 140
- Issue
- 3
- Pages
- 1052-1062
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3049833
- OpenAlex
- W1986577643
- Cited by
- 131
- References
- 39
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 11 · 2023: 10 · 2022: 6 · 2021: 15 · 2020: 2 · 2019: 9 · 2018: 12 · 2017: 7 · 2016: 8 · 2015: 8 · 2014: 8 · 2013: 12 · 2012: 4
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5k08dk088998-03, DK-063491, HL30568)
- National Institute on Alcohol Abuse and Alcoholism (R24 AA12885, P50-AA11999, R24AA012885, P50AA011999)
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL090553, P01HL030568, R01HL066088, HL66088)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08-DK088998, DK063491, T32 DK 07180-30, T32DK007180, P30DK063491)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- liver X receptor, hepatic stellate cells, stellate cell activation, liver fibrosis, lipid metabolism, LXR ligands, chronic liver injury, carbon tetrachloride, bone marrow transplantation, hematopoietic cells, fibrogenic gene expression
- MeSH terms
- Liver X Receptors, Animals, Carbon Tetrachloride, Cells, Cultured, Choline Deficiency, Gene Expression Regulation, Genotype, Liver, Liver Cirrhosis, Experimental, Male, Methionine, Mice, Inbred C57BL, Phenotype, Signal Transduction, Biomarkers, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Inflammation Mediators, Lipid Metabolism, Mice, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury, Orphan Nuclear Receptors
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