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

Shidoji, Yoshihiro

doi:10.1016/j.jlr.2023.100396

Cited by 5 publications

(12 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.

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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%

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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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Phosphatidylserine improves aging sepsis survival, modulates gut microbiome, and prevents sepsis-associated encephalopathy

Xu,

Huang,

Lyu

et al. 2024

Biomedicine & Pharmacotherapy

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Mononuclear phagocyte morphological response to chemoattractants is dependent on geranylgeranyl pyrophosphate

Krauklis,

Hussain,

Murphy

et al. 2024

American Journal of Physiology-Endocrinology and Metabolism

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Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only inhibits de novo synthesis of cholesterol but also isoprenoids that are involved in prenylation, the post-translational lipid modification of proteins. The immunomodulatory effects of statins are broad and often conflicting. Previous work demonstrated that statins increased survival and inhibited myeloid cell trafficking in a murine model of sepsis, but the exact mechanisms underlying this phenomenon were unclear. Herein we investigated the role of prenylation in chemoattractant responses. We found that simvastatin treatment abolished chemoattractant responses induced by stimulation by C5a and FMLP. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene, but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to both chemoattractants was dependent on geranylgeranylation. Proteomic analysis of C15AlkOPP-prenylated proteins identified several geranylgeranylated proteins involved in chemoattractant responses, including RHOA, RAC1, CDC42, and GNG2. Chemoattractant responses in THP-1 human macrophages were also geranylgeranylation dependent. These studies provide data that help clarify paradoxical findings on the immunomodulatory effects of statins. Furthermore, they establish the role of geranylgeranylation in mediating the morphologic response to chemoattractant C5a.

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

Cited by 5 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

Phosphatidylserine improves aging sepsis survival, modulates gut microbiome, and prevents sepsis-associated encephalopathy

Mononuclear phagocyte morphological response to chemoattractants is dependent on geranylgeranyl pyrophosphate

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