ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2021
Collagen release by human hepatic stellate cells requires vitamin C and is efficiently blocked by hydroxylase inhibition.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- Relationship Between Hypovitaminosis C, Obesity, and Features of Metabolic Syndrome-A Narrative Review.Nutrition reviews · 2026Review
- High-throughput human microfluidic organoid-on-a-chip platform for modeling liver diseases and screening nanotherapeutics.Journal of nanobiotechnology · 2026Article
- Altered Bile Acid Transport in Liver Disease.Biomedicines · 2026Review
- Lumican-TLR4 interaction accelerates hepatic fibrosis by activating hepatic stellate cells.Hepatology communications · 2026Article
- Human umbilical cord mesenchymal stem cells attenuate liver fibrosis in mice and inhibit hepatic stellate cell activation by secreting soluble factors.Stem cell research & therapy · 2025Article
- Role of vitamins in the development and treatment of osteoporosis (Review).International journal of molecular medicine · 2025Review
- The metabolic shift of glutaminase 2 to glutaminase 1 promotes LGR5 + progenitor cell proliferation in liver cirrhosis.Cellular and molecular life sciences : CMLS · 2025Article
- Improved Translational Relevance of In Vitro Fibrosis Models by Integrating IOX2-Mediated Hypoxia-Mimicking Pathways.Biomedicines · 2025Article
- High-dose vitamin C as a metabolic treatment of cancer: a new dimension in the era of adjuvant and intensive therapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis.Journal of clinical and translational hepatology · 2025Review
- GMP-compliant, serum-free cultures preserve therapeutic potential of extracellular vesicles from human mesenchymal stromal cells.Frontiers in cell and developmental biology · 2025Article
- Can Nutraceuticals Support the Treatment of MASLD/MASH, and thus Affect the Process of Liver Fibrosis?International journal of molecular sciences · 2024Review
- Emerging therapeutic targets in systemic sclerosis.Journal of molecular medicine (Berlin, Germany) · 2024Review
- Formation and Investigation of Cell-Derived Nanovesicles as Potential Therapeutics against Chronic Liver Disease.Advanced healthcare materials · 2023Article
- Growth differentiation factor 7 autocrine signaling promotes hepatic progenitor cell expansion in liver fibrosis.Stem cell research & therapy · 2023Article
- Structural Insight into the Catalytic Mechanisms of an L-Sorbosone Dehydrogenase.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Article
- Collagen release by human hepatic stellate cells requires vitamin C and is efficiently blocked by hydroxylase inhibition.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Tobacco Smoking and LiverJournal of oncology · 2021Review
- Non-alcoholic Steatohepatitis Pathogenesis, Diagnosis, and Treatment.Frontiers in cardiovascular medicine · 2021Review
Corrections and comments
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Liver fibrosis is characterized by the accumulation of extracellular matrix proteins, mainly composed of collagen. Hepatic stellate cells (HSCs) mediate liver fibrosis by secreting collagen. Vitamin C (ascorbic acid) is a cofactor of prolyl-hydroxylases that modify newly synthesized collagen on the route for secretion. Unlike most animals, humans cannot synthesize ascorbic acid and its role in liver fibrosis remains unclear. Here, we determined the effect of ascorbic acid and prolyl-hydroxylase inhibition on collagen production and secretion by human HSCs. Primary human HSCs (p-hHSCs) and the human HSCscell line LX-2 were treated with ascorbic acid, transforming growth factor-beta (TGFβ) and/or the pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Expression of collagen-I was analyzed by RT-qPCR (COL1A1), Western blotting, and immunofluorescence microscopy. Collagen secretion was determined in the medium by Western blotting for collagen-I and by HPLC for hydroxyproline concentrations. Expression of solute carrier family 23 members 1 and 2 (SLC23A1/SLC23A2), encoding sodium-dependent vitamin C transporters 1 and 2 (SVCT1/SVCT2) was quantified in healthy and cirrhotic human tissue. In the absence of ascorbic acid, collagen-I accumulated intracellularly in p-hHSCs and LX-2 cells, which was potentiated by TGFβ. Ascorbic acid co-treatment strongly promoted collagen-I excretion and enhanced extracellular hydroxyproline concentrations, without affecting collagen-I (COL1A1) mRNA levels. DMOG inhibited collagen-I release even in the presence of ascorbic acid and suppressed COL1A1 and alpha-smooth muscle actin (αSMA/ACTA2) mRNA levels, also under hypoxic conditions. Hepatocytes express both ascorbic acid transporters, while p-hHSCs and LX-2 express the only SVCT2, which is selectively enhanced in cirrhotic livers. Human HSCs rely on ascorbic acid for the efficient secretion of collagen-I, which can be effectively blocked by hydroxylase antagonists, revealing new therapeutic targets to treat liver fibrosis.
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