Geranylgeranoic acid, a bioactive and endogenous fatty acid in mammals: a review

Shidoji, Yoshihiro

doi:10.1016/j.jlr.2023.100396

Cited by 3 publications

(10 citation statements)

References 93 publications

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“…From our studies on HCC prevention, we found that GGA, classified as an acyclic retinoid, induces cell death via pyroptosis in HCC cell lines [16]. Furthermore, we demonstrated that GGA is an endogenous lipid de novo synthesized in the liver from mevalonic acid, rather than a vitamin-like acyclic retinoid [9,85]. Therefore, in this review, we have discussed the mechanism of cell death induction by endogenous lipid GGA, comparing it with saturated fatty acid PA and retinoid ATRA.…”

Section: Gga As An Anti-oncometabolitementioning

confidence: 80%

“…Given the detailed historical background of research on the cell death induction mechanism of GGA in HCC cells [9], here we will summarize all the findings obtained to date and present the proposed mechanism.…”

Section: Mechanism Of Cell Death Induction By Gga In Hepatocellular C...mentioning

confidence: 99%

“…GGA is a branched-chain fatty acid derived from mevalonic acid, with 20 carbon atoms and 4 unsaturated bonds [9]. PA, a saturated fatty acid with 16 carbon atoms, is well known for its lipotoxicity to cells such as hepatocytes [10].…”

Section: Gga-induced Cell Death In Hepatocellular Carcinoma (Hcc) Cel...mentioning

confidence: 99%

“…Since tumors are observed in the liver of C3H/HeN male mice from the first year of life {87}, it is conceivable that GGA administered at this time induces pyroptotic cell death in tumor cells, sweeping them away from the liver. In other words, GGA administered at this time may prevent the onset of liver cancer by plucking out its buds [9].…”

Section: Gga As An Anti-oncometabolitementioning

confidence: 99%

“…Specifically, geranylgeranoic acid (GGA) and its derivative 4,5-didehydroGGA, which possess ligand activity for cellular retinoic acid-binding protein (CRABP) [7] and retinoid receptors (RAR and RXR) [8], as well as differentiation-inducing activity on HCC cell lines [8], were defined as acyclic retinoids. On the other hand, we demonstrated that GGA, unlike all-trans retinoic acid (ATRA), is an 2 endogenous fatty acid synthesized from mevalonic acid in mammalian hepatocytes [9]. Therefore, although GGA is an acyclic retinoid, it cannot be considered a vitamin.…”

Section: Introductionmentioning

confidence: 98%

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Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Preprint

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Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.

show abstract

Section: Gga As An Anti-oncometabolitementioning

confidence: 80%

Section: Mechanism Of Cell Death Induction By Gga In Hepatocellular C...mentioning

confidence: 99%

Section: Gga-induced Cell Death In Hepatocellular Carcinoma (Hcc) Cel...mentioning

confidence: 99%

Section: Gga As An Anti-oncometabolitementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Preprint

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Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Cells

Self Cite

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Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) have emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA’s unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA’s potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA’s anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.

show abstract

Inhibition of Spontaneous Hepatocarcinogenesis by 4,5-Didehydrogeranylgeranoic Acid: Effects of Small-Dose and Infrequent Administration

Omori,

Shidoji,

Moriwaki

2023

IJTM

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Inhibitory effects of 4,5-didehydrogeranylgeranoic acid (dGGA) on the development of tumors were investigated in spontaneous hepatoma mice, C3H/HeNCrj. Experiment 1: Male mice at 8 weeks of age were raised on a basal diet, and then provided with a diet containing 0.02% dGGA from 32 to 91 weeks of age. Experiment 2: dGGA was administered to the animals only once at different time points, from 2 months to 17 months after birth, respectively. Experiment 3: dGGA was administered twice to the mice at different time points: at 5 months and 11 months, and at 8 months and 11 months, respectively. When the inhibitory effects on tumor development were evaluated with the incidences of tumors, average numbers, and weight of tumors per mouse, there was a marked relationship between the time of single or dual dosing and the inhibitory effects of dGGA. The greatest inhibitory effects were observed in Experiment 3 in the group of animals given dGGA at the ages of 8 and 11 months, which were far superior to the results with a large dose of the compounds for a long time. These results might indicate that dGGA administered at the right time in the right amount effectively prevents the development of cancer.

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Geranylgeranoic acid, a bioactive and endogenous fatty acid in mammals: a review

Cited by 3 publications

References 93 publications

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Inhibition of Spontaneous Hepatocarcinogenesis by 4,5-Didehydrogeranylgeranoic Acid: Effects of Small-Dose and Infrequent Administration

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