TLR4, Ethanol, and Lipid Rafts: A New Mechanism of Ethanol Action with Implications for other Receptor-Mediated Effects

University of Massachusetts Medical School, Worcester, MA 01605, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2007; 178(3):1243-9. DOI: 10.4049/jimmunol.178.3.1243
Source: PubMed

ABSTRACT Ethanol (EtOH) is the most widely abused substance in the United States, and it contributes to well-documented harmful (at high dosages) and beneficial (at low dosages) changes in inflammatory and immune responses. Lipid rafts have been implicated in the regulation and activation of several important receptor complexes in the immune system, including the TLR4 complex. Many questions remain about the precise mechanisms by which rafts regulate the assembly of these receptor complexes. Results summarized in this review indicate that EtOH acts by altering the LPS-induced redistribution of components of the TLR4 complex within the lipid raft and that this is related to changes in actin cytoskeleton rearrangement, receptor clustering, and subsequent signaling. EtOH provides an example of an immunomodulatory drug that acts at least in part by modifying lipid rafts, and it could represent a model to probe the relationships between rafts, receptor complexes, and signaling.

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    • "Recent results have demonstrated that recognition of TLR expressed by macrophages or other cell types plays a key role in initiating inflammation, especially in ethanol consumption [8] [9] [10] [11]. TLR4 is the receptor of LPS which activates the downstream signals and various transcription factors in nuclear, such as STAT3, leading to International Immunopharmacology 17 (2013) 184–190 Abbreviations: BA, betulinic acid; BT, betulin; HSCs, hepatic stellate cells; α-SMA, α-smooth muscle actin; LPS, lipopolysaccharide; TLR4, Toll-like receptor4; STAT3, signal transducer and activator of transcription 3; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TG, serum triglyceride; CYP2E1, cytochrome P4502E1; SREBP-1c, sterol regulatory element-binding protein-1c. "
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    ABSTRACT: Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5mg/kg) and BA or BT (20 or 50mg/kg) were applied in vivo, while EtOH (50mM) and BA or BT (12.5 or 25μM) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of α-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies.
    International immunopharmacology 06/2013; 17(2). DOI:10.1016/j.intimp.2013.06.012 · 2.47 Impact Factor
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    • "Ces dernières années, les radeaux lipidiques, microstructures de la membrane plasmique, ont été décrits comme une nouvelle cible de l'exposition à l'éthanol [12] [13]. Parallèlement, les acides gras polyinsaturés oméga 3, présents naturellement dans certains aliments comme les poissons gras, se sont révélés être capables de modifier le microenvironnement physicochimique de ces microstructures avec des effets bénéfiques pour certaines pathologies comme l'inflammation [14] ou le cancer [15]. "
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    ABSTRACT: Alcoholic liver disease is characterized by an early development of steatosis that can progress to steatohepatitis or cirrhosis, but only for 20% of heavy drinkers. Nowadays, description of risk factors and of cellular and molecular mechanisms involved in the disease pathogenesis still remains incomplete. These last years, the plasma membrane microstructures called lipid rafts, were described as a new target for ethanol. Besides, n-3 polyunsaturated fatty acids, naturally present in fat fish, were reported to be able to modulate physically and chemically the lipid raft microenvironment, with beneficial effects towards inflammation or cancer. In this context, the aim of the present review was to establish a link between omega 3-induced membrane alterations and their effects on the molecular mechanisms involved in alcoholic liver disease pathogenesis.
    Nutrition Clinique et Métabolisme 01/2013; DOI:10.1016/j.nupar.2013.10.003 · 0.29 Impact Factor
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    • "cell membranes, SM and cholesterol have been shown to form specific and complex interactions with neurotransmitter receptors like serotonin (Fantini and Barrantes, 2009). Recently it has been suggested that interactions of ethanol molecules with multi-component lipid domains can play a role in immunological functions of the cell as they can potentially disrupt lipid–protein (T-cell receptors) interactions (Szabo et al., 2007; Dolganiuc et al., 2006). Ethanol can potentially affect the functioning of proteins found in such domains by disrupting the SM–cholesterol interactions which can adversely affect the domain stability. "
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    ABSTRACT: The molecular mechanism of ethanol and its effects on neurological function is far from clear. In this study, we investigate the effects of ethanol on various structural and dynamical properties of mixed bilayers consisting of different ratios of dipalmitoylphosphatidylcholine(DPPC), sphingomyelin (SM) and cholesterol that are typical constituents of neural cell membranes (Calderon et al., 1995) using molecular dynamics (MD) simulations. The bilayer properties such as thickness, hydrophobic chain order, and diffusive motion of individual lipids as well collective properties like lateral pressure profiles are affected by the presence of ethanol molecules. The simulations show that the percentage of cholesterol present in the bilayers significantly affects the depth of penetration of ethanol molecules. In particular, presence of very high concentration of cholesterol molecules enhances the rigidity of the bilayer and renders them resistant to the penetration of the ethanol molecules, consistent with experiments. Ethanol molecules compete with cholesterol molecules for hydrogen bonding and disrupt cholesterol-lipid interactions, especially those between SM and cholesterol. Ethanol also molecules affect the lateral pressure profiles in the bilayer systems. These results may have implications in understanding the general anesthetic mechanism and role played by cholesterol on partitioning of such anesthetic/alcohol molecules into cell membranes.
    Chemistry and Physics of Lipids 12/2012; 166(1). DOI:10.1016/j.chemphyslip.2012.11.005 · 2.42 Impact Factor
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