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Cited by 60Hedgehog Signaling Pathway StudiesGrowth Hormone and Insulin-like Growth FactorsLiver physiology and pathology

Hepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levels

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Matz-Soja, Madlen, Aleithe, Susanne, Marbach, Eugenia, Böttger, Jan, Arnold, Katrin, Schmidt-Heck, Wolfgang, Kratzsch, Jürgen, Gebhardt, Rolf·2014·Cell Communication and Signaling
DOI 10.1186/1478-811x-12-11PMC PMC3946028
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Abstract

BACKGROUND: Hedgehog signaling plays an important role in embryonic development, organogenesis and cancer. In the adult liver, Hedgehog signaling in non-parenchymal cells has been found to play a role in certain disease states such as fibrosis and cirrhosis. However, whether the Hedgehog pathway is active in mature healthy hepatocytes and is of significance to liver function are controversial. FINDINGS: Two types of mice with distinct conditional hepatic deletion of the Smoothened gene, an essential co-receptor protein of the Hedgehog pathway, were generated for investigating the role of Hedgehog signaling in mature hepatocytes. The knockout animals (KO) were inconspicuous and healthy with no changes in serum transaminases, but showed a slower weight gain. The liver was smaller, but presented a normal architecture and cellular composition. By quantitative RT-PCR the downregulation of the expression of Indian hedgehog (Ihh) and the Gli3 transcription factor could be demonstrated in healthy mature hepatocytes from these mice, whereas Patched1 was upregulated. Strong alterations in gene expression were also observed for the IGF axis. While expression of Igf1 was downregulated, that of Igfbp1 was upregulated in the livers of both genders. Corresponding changes in the serum levels of both proteins could be detected by ELISA. By activating and inhibiting the transcriptional output of Hedgehog signaling in cultured hepatocytes through siRNAs against Ptch1 and Gli3, respectively, in combination with a ChIP assay evidence was collected indicating that Igf1 expression is directly dependent on the activator function of Gli3. In contrast, the mRNA level of Igfbp1 appears to be controlled through the repressor function of Gli3, while that of Igfbp2 and Igfbp3 did not change. Interestingly, body weight of the transgenic mice correlated well with IGF-I levels in both genders and also with IGFBP-1 levels in females, whereas it did not correlate with serum growth hormone levels. CONCLUSIONS: Our results demonstrate for the first time that Hedgehog signaling is active in healthy mature mouse hepatocytes and that it has considerable importance for IGF-I homeostasis in the circulation. These findings may have various implications for mouse physiology including the regulation of body weight and size, glucose homeostasis and reproductive capacity.

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  • Periportal Hedgehog signalling contributes to defining hepatocyte identity and metabolic zonation by partially counteracting WNT/β-catenin signalling and regulating glucose homeostasis.

    “In addition, periportal Hedgehog signalling contributes to defining hepatocyte identity and metabolic zonation by partially counteracting WNT/β-catenin signalling and regulating glucose homeostasis.53”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [53]

    The Discussion (page unavailable) says Hedgehog disruption appeared to affect liver zonation and that the findings indicate an effect on WNT/β-catenin signalling. It also reports an influence on glucose homeostasis through the IGF axis. It does not establish that the signalling is periportal, defines hepatocyte identity, or counteracts WNT/β-catenin; the zonation finding is more tentative than the citing sentence suggests. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Matz-Soja, M., Aleithe, S., Marbach, E., Böttger, J., Arnold, K., Schmidt-Heck, W., Kratzsch, J., & Gebhardt, R.
Affiliations
Leipzig University (DE)
Corresponding author
Gebhardt, Rolf
ORCID
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2014-02-18
Volume
12
Issue
1
Pages
11-11
ISSN
1478-811X (ISSN-L)
DOI
10.1186/1478-811x-12-11
PMC
PMC3946028
OpenAlex
W2123068738
Cited by
60
References
5
Citations by year
2026: 1 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 8 · 2016: 3 · 2015: 3 · 2014: 4
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Qucosa (Saxon State and University Library Dresden) (submittedVersion, other-oa)
Funders
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung (0315735)
  • Bundesministerium für Forschung und Technologie
  • Universität Leipzig
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
Hedgehog signaling, Smoothened, hepatocytes, insulin-like growth factor I, IGFBP-1, IGFBP-2, IGFBP-3, Gli3, Patched1, Indian hedgehog, IGF axis, body weight regulation, conditional knockout mice, growth hormone
MeSH terms
Patched Receptors, Patched-1 Receptor, Smoothened Receptor, Zinc Finger Protein Gli3, Animals, Cells, Cultured, Female, Homeostasis, Insulin-Like Growth Factor I, Liver, Male, Nerve Tissue Proteins, Receptors, Cell Surface, Signal Transduction, Insulin-Like Growth Factor Binding Protein 1, Hepatocytes, Receptors, G-Protein-Coupled, Mice, Kruppel-Like Transcription Factors, Hedgehog Proteins

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