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Updated: Oct 19, 2025
Author Spotlight: Evaluating Therapeutic Strategies to Enhance Liver Regeneration
Published on: May 24, 2024
Age-Dependent Decrease in Hepatic Geranylgeranoic Acid Content in C3H/HeN Mice and Its Oral Supplementation Prevents
Yuki Tabata1,2, Masahide Omori3, Yoshihiro Shidoji2
1Department of Nutrition, Kiryu University, Midori 379-2392, Gunma, Japan.
Abstract:
Geranylgeranoic acid (GGA) has been developed as a preventive agent against second primary hepatoma. Recently, GGA was reported to induce cell death in human hepatoma cells via TLR4-mediated pyroptosis. We have reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived cells and that endogenous GGA is found in most organs of rats. In addition, we found that upregulation of endogenous GGA levels by zaragozic acid A (ZAA) induced cell death in human hepatoma-derived cells. Therefore, we investigated the age-related changes in hepatic GGA and the possibility of suppressing hepatocarcinogenesis by GGA supplementation using male C3H/HeN mice that spontaneously develop hepatoma. We measured endogenous GGA and mRNA of monoamine oxidase (BMAOB), a key enzyme of GGA biosynthesis, in the liver of male C3H/HeN mice aged 6-93 weeks. We also tried suppressing spontaneous hepatocarcinogenesis by a single administration of GGA to C3H/HeN mice. Hepatic GGA content and Maob mRNA expression level age-dependently decreased in male C3H/HeN mice; some of which produced spontaneous hepatoma in 2 years. A single oral administration of GGA at 11 months of age significantly prevented hepatoma in terms of the number and weight of tumors per mouse at 24 months. Oral supplementation with GGA or geranylgeraniol significantly increased endogenous hepatic GGA contents dose-dependently; and ZAA dramatically upregulated hepatic GGA. In this study; we found an age-dependent decrease in hepatic endogenous GGA in male C3H/HeN mice and efficient prevention of spontaneous hepatoma by a single administration of GGA at 11 months of age.
Insights
Geranylgeranoic acid (GGA) levels decrease with age in mice, but supplementation effectively prevents spontaneous liver cancer (hepatoma). This finding highlights GGA
Area of Science:
- Biochemistry
- Oncology
- Gerontology
Background:
- Geranylgeranoic acid (GGA) shows promise in preventing secondary liver cancer (hepatoma).
- Previous research indicates GGA induces hepatoma cell death via TLR4-mediated pyroptosis.
- Endogenous GGA is biosynthesized from mevalonic acid and found in various organs.
Purpose of the Study:
- To investigate age-related changes in hepatic GGA levels in mice.
- To evaluate the potential of GGA supplementation in suppressing spontaneous hepatocarcinogenesis.
- To explore the link between GGA biosynthesis and age-related liver cancer development.
Main Methods:
- Measurement of endogenous GGA and monoamine oxidase B (MAOB) mRNA in the livers of male C3H/HeN mice across a range of ages (6-93 weeks).
- Administration of GGA to assess its effect on spontaneous hepatocarcinogenesis.
- Dose-dependent analysis of GGA and geranylgeraniol supplementation on hepatic GGA content.
Main Results:
- Hepatic GGA content and MAOB mRNA expression decreased with age in male C3H/HeN mice.
- A single oral GGA administration at 11 months significantly reduced hepatoma incidence and size at 24 months.
- Oral GGA and geranylgeraniol supplementation dose-dependently increased hepatic GGA; zaragozic acid A (ZAA) markedly upregulated it.
Conclusions:
- Hepatic GGA levels decline with age in male C3H/HeN mice.
- Early-life GGA administration is an effective strategy for preventing spontaneous hepatoma.
- Maintaining adequate GGA levels may be crucial for mitigating age-related liver cancer risk.
