Kupffer cells mediate leptin-induced liver fibrosis
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Background & aims Leptin has profibrogenic effects in liver, although the mechanisms of this process are unclear. We sought to elucidate the direct and indirect effects of leptin on hepatic stellate cells (HSCs).Methods HSCs from Sprague-Dawley rats were exposed to leptin and expression of collagen-I, tissue inhibitor of matrix metalloproteinases-1 (TIMP1), transforming growth factor beta1 (TGF-beta1), and connective tissue growth factor (CTGF/CCN2) was assessed. The effects of medium from Kupffer cells (KCs) and sinusoidal endothelial cells (SECs) following leptin were evaluated in HSCs; alpha-smooth muscle actin (alphaSMA) production and KC signaling were analyzed.Results HSCs were not activated by incubation with leptin. However, HSCs cultured with medium taken from KCs that were incubated with leptin had increased expression of collagen I, TIMP1, TGF-beta1, and CTGF/CCN2, as well as alphaSMA protein levels and proliferation. These effects were leptin receptor dependent because conditioned medium from KCs isolated from leptin receptor-deficient Zucker (fa/fa) rats did not activate HSCs. In KCs incubated with leptin, messenger RNA and protein expression of TGF-beta1 and CTGF/CCN2 increased. Leptin potentiated signal transducer and activator of transcription 3, AKT, and extracellular signal-related kinase 1/2 phosphorylation in KCs and increased AP-1 and nuclear factor-kappaB DNA binding. Finally, addition of anti-TGF-beta to KC-conditioned medium inhibited HSC expression of collagen I, TIMP1, and CTGF/CCN2, whereas signal transducer and activator of transcription 3 inhibitor attenuated TGF-beta1 production by KC.Conclusions Leptin mediates HSC activation and liver fibrosis through indirect effects on KC; these effects are partly mediated by TGF-beta1.
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Leptin, produced by adipocytes and increased in obesity, amplifies pro-fibrotic signalling during liver injury, including increased production of TGF-β1 from KCs and direct effects on HSCs.
“The adipokine, Leptin, which is produced by adipocytes and increased in obesity, amplifies pro-fibrotic signalling during liver injury in several ways, including increased production of TGF-β1 from KCs,157 and direct effects on HSCs.158”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [157]
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References 48 · Cited by 210
- Authors
- Wang, J., Leclercq, I., Brymora, J. M., Xu, N., Ramezani–Moghadam, M., London, R. M., Brigstock, D., & George, J.
- Affiliations
- The University of Sydney (AU)
- UCLouvain (BE)
- Corresponding author
- George, Jacob
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 137
- Issue
- 2
- Pages
- 713-723.e1
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2757122
- OpenAlex
- W2119117909
- Cited by
- 210
- References
- 48
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 9 · 2023: 16 · 2022: 8 · 2021: 14 · 2020: 16 · 2019: 5 · 2018: 12 · 2017: 6 · 2016: 11 · 2015: 13 · 2014: 19 · 2013: 16 · 2012: 12
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (5R01AA016003)
- University of Sydney
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- leptin, liver fibrosis, Kupffer cells, hepatic stellate cells, TGF-β1, TIMP-1, leptin receptor, hepatocyte activation, AP-1, NF-κB, Akt signaling, ERK signaling, type I collagen, sinusoidal endothelial cells
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Hydrogen Peroxide, Immunohistochemistry, Kupffer Cells, Liver Cirrhosis, Male, Random Allocation, Reference Values, Sensitivity and Specificity, Immunoblotting, Up-Regulation, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Cell Proliferation, Rats, Transforming Growth Factor beta1, Hepatic Stellate Cells
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