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Amino acids regulate hepatocyte proliferation through modulation of cyclin D1 expression
Christopher J Nelsen1, David G Rickheim, Melissa M Tucker
1Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55415, USA.
The Journal of Biological Chemistry
|May 9, 2003
Summary
Nonessential amino acids (NEAA) are crucial for cell cycle progression in hepatocytes. NEAA deprivation inhibits cyclin D1 expression, halting cell proliferation, but cyclin D1 can overcome this arrest.
Area of Science:
- Hepatology
- Cell Biology
- Molecular Biology
Background:
- Amino acid regulation of the cell cycle is not fully understood.
- Hepatocyte proliferation is vital for liver function and regeneration.
Purpose of the Study:
- To investigate how amino acids and protein intake control hepatocyte proliferation.
- To identify key molecular targets in amino acid-mediated cell cycle regulation.
Main Methods:
- Hepatocyte culture and deprivation of essential and nonessential amino acids.
- Analysis of cell cycle protein expression and gene transcription.
- In vivo studies using protein-deprived mice undergoing partial hepatectomy.
- Gene transfection experiments with cyclin D1 and cyclin E.
Main Results:
- Nonessential amino acid (NEAA) deprivation inhibited hepatocyte cell cycle progression and down-regulated proliferation proteins.
- NEAA withdrawal affected a distinct cell cycle checkpoint, inhibiting entry into S phase.
- Cyclin D1 expression was transcriptionally inhibited by NEAA deprivation, and its reintroduction overcame cell cycle arrest.
- In vivo, protein deprivation impaired hepatocyte proliferation and cyclin D1 expression, which was restored by cyclin D1 transfection.
Conclusions:
- Cyclin D1 is a critical mediator and target of amino acid signaling in hepatocytes.
- Amino acids, particularly NEAA, play a significant role in regulating hepatocyte proliferation through cyclin D1.
- Targeting cyclin D1 may offer therapeutic strategies for liver regeneration and growth.