Influence of the Membrane Lipid Structure on Signal Processing via G Protein-Coupled Receptors

Yang, Qing; Alemany, Regina; Casas, J. Manuel; Kitajka, Klára; Lanier, Stephen M.; Escribá, Pablo V.

doi:10.1124/mol.105.011692

Cited by 80 publications

(69 citation statements)

References 45 publications

(58 reference statements)

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“…Long-term intake of high doses of VOO reduces BP and the risk of developing hypertension (13)(14)(15)(16). At the molecular level, OA and VOO regulate G protein-associated signaling both in vivo (in humans) and in cell culture (1,17). Interestingly, the hypotensive effect of 2-hydroxyoleic acid involves changes in the same signaling pathways as those affected by OA (18,19).…”

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confidence: 99%

“…Free or esterified, OA can modify the biophysical properties of membranes, specifically increasing the nonlamellar (H II ) phase propensity of the membrane (2, 3). In turn, this modification affects the docking of important membrane-associated signal transduction proteins involved in controlling BP, such as G proteins (1,24,25). In fact, altered levels and function of G proteins have been reported in both hypertensive humans (26,27) and experimental models of hypertension (28,29).…”

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confidence: 99%

“…We have recently shown that OA, but not its structural analogues elaidic and stearic acid, regulates the activity of the ␣ 2A/D -adrenoreceptor/G protein/adenylyl cyclase-cAMP/PKA system by modulating the structure of plasma membrane lipids (1). Free or esterified, OA can modify the biophysical properties of membranes, specifically increasing the nonlamellar (H II ) phase propensity of the membrane (2, 3).…”

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confidence: 99%

“…Recent studies showed that the activity of the adrenoreceptor signaling pathway can be regulated by oleic acid (OA) (cis-18:1n-9) (1), specifically because of the effect of this fatty acid on the structure of cell membranes (1,2). However, similar modulation of G protein-coupled receptor signaling is not induced by structurally different but closely related fatty acids with identical or similar chemical composition, such as elaidic acid (trans-18:1n-9) or stearic acid (18:0).…”

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Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Terés

Barceló‐Coblijn

Benet

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

436

266

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Numerous studies have shown that high olive oil intake reduces blood pressure (BP). These positive effects of olive oil have frequently been ascribed to its minor components, such as ␣-tocopherol, polyphenols, and other phenolic compounds that are not present in other oils. However, in this study we demonstrate that the hypotensive effect of olive oil is caused by its high oleic acid (OA) content (Ϸ70 -80%). We propose that olive oil intake increases OA levels in membranes, which regulates membrane lipid structure (HII phase propensity) in such a way as to control G protein-mediated signaling, causing a reduction in BP. This effect is in part caused by its regulatory action on G protein-associated cascades that regulate adenylyl cyclase and phospholipase C. In turn, the OA analogues, elaidic and stearic acids, had no hypotensive activity, indicating that the molecular mechanisms that link membrane lipid structure and BP regulation are very specific. Similarly, soybean oil (with low OA content) did not reduce BP. This study demonstrates that olive oil induces its hypotensive effects through the action of OA.aorta ͉ fatty acids ͉ membrane structure ͉ signaling proteins ͉ membrane-lipid therapy

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Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Terés

Barceló‐Coblijn

Benet

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

436

266

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“…In this context, anthracyclines that are unable to enter cancer cells or bind to DNA still have strong antitumor activity (6). Indeed, those used in human therapy regulate plasma membrane structure, and they induce changes in the localization and activity of important peripheral signaling proteins, such as G proteins and PKC (4,7,8). This mode of action also appears to be responsible for the activity of hexamethylene bisacetamide against cancers (9,10).…”

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Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Lladó¹,

Terés

Higuera

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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␣-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.anticancer ͉ DNA ͉ membrane-lipid therapy ͉ neoplasia ͉ nutrigenetics 2 -Hydroxyoleic acid (HOA) is a potent anticancer drug whose molecular mechanism of action is still not fully understood. Although HOA induces cell cycle exit in human lung cancer (A549) cells (1), it induces apoptosis in human leukemia cells (2). The IC 50 of this drug for most cancer cells studied is in the range of 30-150 M, whereas its IC 50 in normal cells is over 5,000 M (2). Thus, this drug does not produce toxicity at therapeutic doses despite acting efficiently in cell and animal models of human cancers (2, 3). Hence, it is important to define the mode of action of this compound and whether common molecular events underlie its therapeutic effects and the regression of different types of cancer.HOA was developed on the basis that the lipid composition and structure of the plasma membrane can be altered by certain antitumor drugs and that these modifications are involved in their action against cancer (4, 5). In this context, anthracyclines that are unable to enter cancer cells or bind to DNA still have strong antitumor activity (6). Indeed, those used in human therapy regulate plasma membrane structure, and they induce changes in the localization and activity of important peripheral signaling proteins, such as G proteins and PKC (4,7,8). This mode of action also appears to be responsible for the activity of hexamethylene bisacetamide against cancers (9, 10).In the search for molecules capable of i...

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Molecular mechanisms of the effects of olive oil and other dietary lipids on cancer

Escrich

Moral

Grau

et al. 2007

Molecular Nutrition Food Res

126

105

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Cancer is one of the main causes of mortality worldwide. Geographical differences in incidence rates suggest a key effect of environmental factors, especially diet, in its aetiology. Epidemiologic and experimental studies have found a role of dietary lipids in cancer, particularly breast, colorectal, and prostate cancers. Their incidence in the Mediterranean countries, where the main source of fat is olive oil, is lower than in other areas of the world. Human studies about the effects of dietary lipids are little conclusive, probably due to methodological issues. On the other hand, experimental data have clearly demonstrated that the influence of dietary fats on cancer depends on the quantity and the type of lipids. Whereas a high intake of n-6 PUFA and saturated fat has tumor-enhancing effects, n-3 PUFA, conjugated linoleic acid and gamma-linolenic acid have inhibitory effects. Data regarding MUFA have not always been conclusive, but high olive oil diets seem to have protective effects. Such effects can be due to oleic acid, the main MUFA in olive oil, and to certain minor compounds such as squalene and phenolic compounds. This work aims to review the current knowledge about the relationship between dietary lipids and cancer, with a special emphasis on olive oil, and the molecular mechanisms underlying these effects: modifications on the carcinogenesis stages, hormonal status, cell membrane structure and function, signal transduction pathways, gene expression, and immune system.

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Influence of the Membrane Lipid Structure on Signal Processing via G Protein-Coupled Receptors

Cited by 80 publications

References 45 publications

Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Molecular mechanisms of the effects of olive oil and other dietary lipids on cancer

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