Cell cycle dependence on the mevalonate pathway: Role of cholesterol and non-sterol isoprenoids

Lasunción, Miguel A.; Martı́nez-Botas, Javier; Martín-Sánchez, Covadonga; Busto, Rebeca; Gómez-Coronado, Diego

doi:10.1016/j.bcp.2021.114623

Cited by 15 publications

(19 citation statements)

References 285 publications

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“…AY9944 has been identified as a DHCR7 inhibitor, but is also known to target various molecules through off-target effects 17 . In particular, AY9944 inhibits DHCR14a (encoded by TM7SF2 ), DHCR14b ( LBR ), or sterolΔ8-Δ7 isomerase ( EBP ), which are upstream of DHCR7 in the cholesterol synthesis pathway (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis

Yamada,

Karasawa,

Ito

et al. 2024

Nat Commun

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Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

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Section: Resultsmentioning

confidence: 99%

Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis

Yamada,

Karasawa,

Ito

et al. 2024

Nat Commun

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“…( R )-Mevalonolactone, a lactone belonging to the δ-valerolactone class, plays a pivotal role as an essential intermediate in the mevalonate biosynthetic pathway. This biosynthetic route is crucial for synthesizing isoprenoids, versatile compounds with diverse functions in various cellular processes [ 48 , 49 ]. Notably, ( R )-mevalonolactone has been isolated from different pathogenic and non-pathogenic fungi cultivated in vitro, including Colletotrichum lupini , Diaporthaceae sp.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Secondary Metabolites Produced by Ascochyta fabae under In Vitro Conditions and Their Phytotoxicity on the Primary Host, Vicia faba, and Related Legume Crops

Barilli,

Reveglia,

Agudo-Jurado

et al. 2023

Toxins

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Ascochyta blight, caused by Ascochyta fabae, poses a significant threat to faba bean and other legumes worldwide. Necrotic lesions on stems, leaves, and pods characterize the disease. Given the economic impact of this pathogen and the potential involvement of secondary metabolites in symptom development, a study was conducted to investigate the fungus’s ability to produce bioactive metabolites that might contribute to its pathogenicity. For this investigation, the fungus was cultured in three substrates (Czapek-Dox, PDB, and rice). The produced metabolites were analyzed by NMR and LC-HRMS methods, resulting in the dereplication of seven metabolites, which varied with the cultural substrates. Ascochlorin, ascofuranol, and (R)-mevalonolactone were isolated from the Czapek-Dox extract; ascosalipyrone, benzoic acid, and tyrosol from the PDB extract; and ascosalitoxin and ascosalipyrone from the rice extract. The phytotoxicity of the pure metabolites was assessed at different concentrations on their primary hosts and related legumes. The fungal exudates displayed varying degrees of phytotoxicity, with the Czapek-Dox medium’s exudate exhibiting the highest activity across almost all legumes tested. The species belonging to the genus Vicia spp. were the most susceptible, with faba bean being susceptible to all metabolites, at least at the highest concentration tested, as expected. In particular, ascosalitoxin and benzoic acid were the most phytotoxic in the tested condition and, as a consequence, expected to play an important role on necrosis’s appearance.

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“…RHO GTPases are essential for the degradation of p27 Kip1 and subsequent activation of cyclin‐dependent kinases (CDK) that mediate cell cycle progression 128 . Treatments of GGTase1 inhibitors cause cells to accumulate in G1 129 . Due to the vast catalog of GGTase1 substrates and the overlap of downstream effectors between different GTPases, it is difficult to define exact mechanisms by which GGTase1 inhibitors lead to cell cycle arrest, but the best studied substrates are the RHO GTPases RHO, RAC and CDC42.…”

Section: Mevalonate‐derived Metabolites Regulate T Cell Signalingmentioning

confidence: 99%

Decoding the crosstalk between mevalonate metabolism and T cell function

Kennewick

Bensinger

2023

Immunological Reviews

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SummaryThe mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.

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Cell cycle dependence on the mevalonate pathway: Role of cholesterol and non-sterol isoprenoids

Cited by 15 publications

References 285 publications

Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis

Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis

Comparative Analysis of Secondary Metabolites Produced by Ascochyta fabae under In Vitro Conditions and Their Phytotoxicity on the Primary Host, Vicia faba, and Related Legume Crops

Decoding the crosstalk between mevalonate metabolism and T cell function

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