Succinate induces hepatic fibrogenesis by promoting activation, proliferation, and migration, and inhibiting apoptosis of hepatic stellate cells
Abstract
Liver fibrosis is a progressive pathological process that accompanies wound healing; however, therapeutics for reversing hepatic fibrosis are unavailable. Activation of hepatic stellate cells (HSCs) play a critical role in liver fibrosis. Recent reports showed that succinate and its receptor, G-protein coupled receptor 91 (GPR91), act as signaling molecules during the activation of HSCs. However, the role of succinate in proliferation, apoptosis, and migration of HSCs has not been studied. In this study, we determined whether succinate regulates proliferation, apoptosis, and migration of HSCs and induces liver fibrosis in a mouse model. Succinate treatment not only induced activation of HSCs, but also increased the proliferation and migration of LX-2 HSCs and inhibited apoptosis. To investigate whether succinate causes hepatic fibrosis, 100 mg/kg succinate or control PBS was administered by intraperitoneal injection to mice once a day for four weeks. There were significant molecular changes such as increased α-SMA and collagen type 1 production and increased production of inflammatory cytokines such as IL-6 and TNF-α, but not TGF-β, in the succinate-treated group compared to the control group. However, no morphological changes were observed in Masson's trichrome staining. In conclusion, the present study demonstrated that succinate induces activation, proliferation, and migration of HSCs and attenuates apoptosis in LX-2 HSCs. Therefore, inhibition of succinate accumulation may be an effective method for reversing liver fibrosis by controlling HSC survival and growth.
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Tissue macrophages are important producers of T cell- and fibroblast-recruiting chemokines that orchestrate the development of the fibrotic niche.
“Tissue macrophages are also important producers of T cell- and fibroblast-recruiting chemokines that orchestrate the development of the fibrotic niche67.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [67]
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Fibrosis: from mechanisms to medicines
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- Authors
- Park, S. Y., Le, C. T., Sung, K. Y., Choi, D. H., & Cho, E.-H.
- Affiliations
- Kangwon National University (KR)
- Corresponding author
- Cho, Eun-Hee
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 496
- Issue
- 2
- Pages
- 673-678
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2788651231
- Cited by
- 58
- References
- 20
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 4 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NRF (2016R1C1B2011968)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- succinic acid, liver fibrosis, hepatic stellate cells, hepatic stellate cell activation, HSC proliferation, HSC migration, apoptosis, GPR91, succinate receptor, LX-2 cells, collagen type 1, alpha-smooth muscle actin, inflammatory cytokines, interleukin-6, TNF-α
- MeSH terms
- Actins, Animals, Cell Line, Cell Movement, Humans, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Apoptosis, Succinic Acid, Cell Proliferation, Hepatic Stellate Cells
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