Evidence for LKB1/AMP-activated protein kinase/endothelial nitric oxide synthase cascade regulated by hepatocyte growth factor, S-adenosylmethionine, and nitric oxide in hepatocyte proliferation
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UNLABELLED: S-adenosylmethionine (SAMe) is involved in numerous complex hepatic processes such as hepatocyte proliferation, death, inflammatory responses, and antioxidant defense. One of the most relevant actions of SAMe is the inhibition of hepatocyte proliferation during liver regeneration. In hepatocytes, SAMe regulates the levels of cytoplasmic HuR, an RNA-binding protein that increases the half-life of target messenger RNAs such as cyclin D1 and A2 via inhibition of hepatocyte growth factor (HGF)-mediated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Because AMPK is activated by the tumor suppressor kinase LKB1, and AMPK activates endothelial nitric oxide (NO) synthase (eNOS), and NO synthesis is of great importance for hepatocyte proliferation, we hypothesized that in hepatocytes HGF may induce the phosphorylation of LKB1, AMPK, and eNOS through a process regulated by SAMe, and that this cascade might be crucial for hepatocyte growth. We demonstrate that the proliferative response of hepatocytes involves eNOS phosphorylation via HGF-mediated LKB1 and AMPK phosphorylation, and that this process is regulated by SAMe and NO. We also show that knockdown of LKB1, AMPK, or eNOS with specific interference RNA (iRNA) inhibits HGF-mediated hepatocyte proliferation. Finally, we found that the LKB1/AMPK/eNOS cascade is activated during liver regeneration after partial hepatectomy and that this process is impaired in mice treated with SAMe before hepatectomy, in knockout mice deficient in hepatic SAMe, and in eNOS knockout mice. CONCLUSION: We have identified an LKB1/AMPK/eNOS cascade regulated by HGF, SAMe, and NO that functions as a critical determinant of hepatocyte proliferation during liver regeneration after partial hepatectomy.
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NOS3 is expressed at highest relative abundance in vascular endothelium, but is also found in neurons, epithelial cells, cardiomyocytes, adipocytes, and hepatocytes.
“NOS3 (commonly called endothelial NOS or eNOS) is expressed to highest relative abundance in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67, 68] and hepatocytes [69-71].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [70]
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“most abundant in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67,68] and hepatocytes [69–71].”
BackgroundThe evolving role of liver sinusoidal endothelial cells in liver health and disease
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- Authors
- Vázquez-Chantada, M., Ariz, U., Varela-Rey, M., Embade, N., Martínez-Lopez, N., Fernández-Ramos, D., Gómez-Santos, L., Lamas, S., Lu, S. C., Martínez-Chantar, L. M., & Mato, J. M.
- Affiliations
- CIC bioGUNE (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- University of Southern California (US)
- Corresponding author
- Mato, José M.
- Venue
- Hepatology
- Published
- 2009-02
- Volume
- 49
- Issue
- 2
- Pages
- 608-617
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2635424
- OpenAlex
- W2050778099
- Cited by
- 76
- References
- 55
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 7 · 2012: 9
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA013847, AA13847)
- National Center for Complementary and Integrative Health (R01AT001576, AT-1576)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- LKB1, AMPK, endothelial nitric oxide synthase, hepatocyte growth factor, S-adenosylmethionine, nitric oxide, hepatocyte proliferation, liver regeneration, partial hepatectomy, HuR, cyclin D1, cyclin D2
- MeSH terms
- Animals, Cell Division, DNA Replication, Hepatectomy, Homeostasis, Liver Regeneration, Male, Mice, Inbred C57BL, Phosphorylation, Protein Serine-Threonine Kinases, Microscopy, Confocal, Gene Silencing, Hepatocytes, Mice, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases
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