A rapid increase in lysophospholipids after geranylgeranoic acid treatment in human hepatoma-derived HuH-7 cells revealed by metabolomics analysis

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

“…5 ), while lyso-PC containing dihomo-γ-linolenic acid (C20:3) increased later. Interestingly, as with the addition of PA, lyso-PC containing PA showed a rapid and transient increase (peaking at 2 h after GGA addition at the latest) followed by a slow increase, reaching the highest concentration among the increased lyso-PLs ( 62 ). Therefore, the same mechanism of lipotoxicity exhibited by PA may be at work in the induction of cell death of hepatoma cells by GGA [XI].…”

“…5 Timeline of the cellular events during GGA-induced cell death of human hepatoma HuH-7 cells. The increase in intracellular lyso-PC and lyso-PE after GGA treatment was detected by metabolomics analysis without preconception ( 62 ). The increases in intracellular calcium ions and mitochondrial superoxide after GGA treatment were quantified in time series by observing a culture system of HuH-7 cells with Fluo-4 AM or MitoSox Red incorporated using a laser scanning confocal fluorescence microscope and collecting live cell images in time-lapse ( 63 ).…”

“…There is no experimental evidence that GGA [XI] is incorporated into lyso-PLs or DAGs as in the case of PA. However, of note, we recently detected without any preconceptions by comprehensive metabolomics analysis that immediately after treatment of HuH-7 cells with 10 μM GGA [XI], nine molecular species of lyso-PLs are overwhelmingly increased compared to other cellular metabolites ( 62 ). Moreover, lysophosphatidylcholine (lyso-PC) containing one of PA (C16:0), palmitoleic acid (C16:1), or arachidonic acid (C20:4) and lysophosphatidylethanolamine containing C20:4 increased most quickly (see Fig.…”

“…However, unlike the case of PA, GGA [XI] cannot be directly metabolized to PA-containing lyso-PC, which raises the question of what mechanism allows GGA [XI] to increase PA-containing lyso-PC. To answer this question, based on the characterization of the molecular species of the increased lyso-PLs, we suspect that GGA [XI] may be responsible for the decrease in ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) or autotaxin activity ( 62 ). ENPP2, an enzyme that acts on lyso-PLs to produce lysophosphatidic acid, plays a very important role in hepatoma development ( 86 ), including the growth of hepatitis B virus ( 87 ) and hepatitis C virus ( 88 ), and high-grade hepatomas are reported to have high ENPP2 expression ( 89 ).…”

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

“… 2 hours: A transient increase in lysophosphatidylcholine containing PA and palmitoleic acid (lysoPC [16:0]; lysoPC [16:1]) is observed. In contrast, a significant increase in lysoPC (lysoPC [20:4]) and lysophosphatidylethanolamine (lysoPE [20:4]) containing arachidonic acid is observed, and then these lysophospholipids (lysoPLs) remain at high levels and continue to increase gradually until 24 h [19].  3 hours: Immunofluorescence staining of GSDMD reveals signals mainly in the nucleus in control cells, but in GGA-treated cells, the signals are also detected in the plasma membrane [16].…”