Deoxycholic Acid Induces Intracellular Signaling through Membrane Perturbations

Jean-Louis, Samira; Akare, Sandeep; Ali, M. Ahad; Mash, Eugene A.; Meuillet, Emmanuelle J.; Martinez, Jesse D.

doi:10.1074/jbc.m506710200

Cited by 111 publications

(91 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DCA markedly elevated the level of PA but decreased the level of PIP 2 in the PM of Caco-2 cells (Fig 1B). Changes in the PM lipid levels were unlikely to be caused by alterations in lipid metabolism because of the short DCA treatment time; DCA incubation of at least 1h is required to induce any meaningful change in lipid metabolism [24]. Further, DCA caused no change in cholesterol aggregation pattern and PM level (Fig 1A and 1B), consistent with the view that changes lipid levels observed in Fig 1 were independent of lipid metabolism.…”

Section: Resultssupporting

confidence: 76%

See 1 more Smart Citation

Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Luan¹,

Estes²,

Zhang³

et al. 2018

PLoS ONE

View full text Add to dashboard Cite

Bile acids are critical biological detergents in the gastrointestinal tract and also act as messengers to regulate a multitude of intracellular signaling events, including mitogenic signaling, lipid metabolism and endo/exocytosis. In particular, bile acids stimulate many receptors and ion channels on the cell surface, the mechanisms of which are still poorly understood. Membrane-associating proteins depend on the local spatial distribution of lipids in the plasma membrane (PM) for their function. Here, we report that the highly amphipathic secondary bile acid deoxycholic acid (DCA), a major constituent in the human bile, at doses <1μM enhances the nanoclustering and the PM localization of phosphatidic acid (PA) but disrupts the local segregation of phosphatidylserine in the basolateral PM of the human colorectal adenocarcinoma Caco-2 cells. PA is a key structural component of the signaling nano-domains of epidermal growth factor receptor (EGFR) on the cell surface. We show that DCA promotes the co-localization between PA and EGFR, the PA-driven EGFR dimerization/oligomerization and EGFR signaling. Depletion of PA abolishes the stimulatory effects of DCA on the EGFR oligomerization and signaling. This effect occurs in the cultured Caco-2 cells and the ex vivo human intestinal enteroids. We propose a novel mechanism, where the amphiphilic DCA monomers alter the nano-assemblies of anionic phospholipids and in turn change the dynamic structural integrity of the lipid-driven oligomerization of cell surface receptors and their signal transduction.

show abstract

Section: Resultssupporting

confidence: 76%

“…DCA robustly activates EGFR-dependent MAPK signaling in many GI cell lines [24, 26, 27]. We then used EGFR as an example to examine how the DCA-induced changes in PM lipids potentially contribute to the function of the surface receptors.…”

Section: Resultsmentioning

confidence: 99%

Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Luan¹,

Estes²,

Zhang³

et al. 2018

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…To evaluate the role of BL0920 in bile extrusion, we used fluorescently tagged ursodeoxycholic acid (UDCA) (15). In short, tDE3 cells carrying empty pETblue-1 or the plasmid containing the BL0920 gene (pETBL0920) were grown in LB broth, supplemented with antibiotics and glucose as indicated above, to an OD 600 of 0.4.…”

Section: Methodsmentioning

confidence: 99%

Bile-Inducible Efflux Transporter from Bifidobacterium longum NCC2705, Conferring Bile Resistance

Gueimonde

Garrigues

Sinderen

et al. 2009

Appl Environ Microbiol

View full text Add to dashboard Cite

Bifidobacteria are normal inhabitants of the human gut. Some strains of this genus are considered health promoting or probiotic, being included in numerous food products. In order to exert their health benefits, these bacteria must overcome biological barriers, including bile salts, to colonize and survive in specific parts of the intestinal tract. The role of multidrug resistance (MDR) transporters in bile resistance of probiotic bacteria and the effect of bile on probiotic gene expression are not fully understood. In the present study, the effect of subinhibitory concentrations of bile on the expression levels of predicted MDR genes from three different bifidobacterial strains, belonging to Bifidobacterium longum subsp. longum, Bifidobacterium breve, and Bifidobacterium animalis subsp. lactis, was tested. In this way, two putative MDR genes whose expression was induced by bile, BL0920 from B. longum and its homolog, Bbr0838, from B. breve, were identified. The expression of the BL0920 gene in Escherichia coli was shown to confer resistance to bile, likely to be mediated by active efflux from the cells. To the best of our knowledge, this represents the first identified bifidobacterial bile efflux pump whose expression is induced by bile.

show abstract

“…Bile acids have been shown to interact directly with specific receptors (30,31). These steroids can also initiate cellular signaling through nonspecific membrane perturbations (32), and evidence exists showing that other simple detergents (i.e. Triton X-100) are capable of inducing caspase cleavage nonspecifically with resultant apoptosis (33).…”

mentioning

confidence: 99%

Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines

Katona

Anant

Covey

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Bile acids are steroid detergents that are toxic to mammalian cells at high concentrations; increased exposure to these steroids is pertinent in the pathogenesis of cholestatic disease and colon cancer. Understanding the mechanisms of bile acid toxicity and apoptosis, which could include nonspecific detergent effects and/or specific receptor activation, has potential therapeutic significance. In this report we investigate the ability of synthetic enantiomers of lithocholic acid (ent-LCA), chenodeoxycholic acid (ent-CDCA), and deoxycholic acid (ent-DCA) to induce toxicity and apoptosis in HT-29 and HCT-116 cells. Natural bile acids were found to induce more apoptotic nuclear morphology, cause increased cellular detachment, and lead to greater capase-3 and -9 cleavage compared with enantiomeric bile acids in both cell lines. In contrast, natural and enantiomeric bile acids showed similar effects on cellular proliferation. These data show that bile acid-induced apoptosis in HT-29 and HCT-116 cells is enantiospecific, hence correlated with the absolute configuration of the bile steroid rather than its detergent properties. The mechanism of LCA-and ent-LCA-induced apoptosis was also investigated in HT-29 and HCT-116 cells. These bile acids differentially activate initiator caspases-2 and -8 and induce cleavage of full-length Bid. LCA and ent-LCA mediated apoptosis was inhibited by both pan-caspase and selective caspase-8 inhibitors, whereas a selective caspase-2 inhibitor provided no protection. LCA also induced increased CD95 localization to the plasma membrane and generated increased reactive oxygen species compared with ent-LCA. This suggests that LCA/ ent-LCA induce apoptosis enantioselectively through CD95 activation, likely because of increased reactive oxygen species generation, with resulting procaspase-8 cleavage.Bile acids are physiologic steroids that are necessary for the proper absorption of fats and fat-soluble vitamins. Their ability to aid in these processes is largely due to their amphipathic nature and thus their ability to act as detergents. Despite the beneficial effects, high concentrations of bile acids are toxic to cells (1-11).High fat western diets induce extensive recirculation of the bile acid pool, resulting in increased exposure of the colonic epithelial cells to these toxic steroids (12, 13). A high fat diet is also a risk factor for colon carcinogenesis; increased bile acid exposure is responsible for some of this risk. Bile acids can contribute to both colon cancer formation and progression, and their effects on colonic proliferation and apoptosis aid this process by disrupting the balance between cell growth and cell death, as well as helping to select for bile acid-resistant cells (14,15).In colonocyte-derived cell lines bile acid-induced apoptosis is thought to proceed through mitochondrial destabilization with resulting mitochondrial permeability transition formation and cytochrome c release as well as generation of oxidative stress (1, 9 -11). Bile acid-induced apoptosis has also ...

show abstract

Deoxycholic Acid Induces Intracellular Signaling through Membrane Perturbations

Cited by 111 publications

References 67 publications

Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Bile-Inducible Efflux Transporter from Bifidobacterium longum NCC2705, Conferring Bile Resistance

Characterization of Enantiomeric Bile Acid-induced Apoptosis in Colon Cancer Cell Lines

Contact Info

Product

Resources

About