Mechanisms underlying the anti-aging and anti-tumor effects of lithocholic bile acid

Abstract

Bile acids are cholesterol-derived bioactive lipids that play essential roles in the maintenance of a heathy lifespan. These amphipathic molecules with detergent-like properties display numerous beneficial effects on various longevity- and healthspan-promoting processes in evolutionarily distant organisms. Recent studies revealed that lithocholic bile acid not only causes a considerable lifespan extension in yeast, but also exhibits a substantial cytotoxic effect in cultured cancer cells derived from different tissues and organisms. The molecular and cellular mechanisms underlying the robust anti-aging and anti-tumor effects of lithocholic acid have emerged. This review summarizes the current knowledge of these mechanisms, outlines the most important unanswered questions and suggests directions for future research.

Figure 1

Outline of a network governing lipid metabolism and transport within the endoplasmic reticulum (ER), lipid droplets (LD), peroxisomes, mitochondria and the plasma membrane (PM). The proper functioning of this intricate network is necessary for maintaining lipid homeostasis in all of these cellular organelles and membranes. The PA, PS, PC and PI classes of phospholipids are synthesized exclusively in the ER; these are then transported to mitochondria via mitochondria-ER junctions and to the PM via PM-ER junctions. The PE and CL classes of phospholipids are formed only in the inner mitochondrial membrane (IMM); PE is then transported from mitochondria to the ER via mitochondria-ER junctions and from the ER to the PM via PM-ER junctions. The neutral lipids TAG and EE are synthesized in the ER and then deposited within LD. The lipolytic hydrolysis of TAG and EE in LD generates FFA; these then get imported and oxidized by peroxisomes. Peroxisomally produced acetyl-CoA is converted to citrate and acetyl-carnitine, whose subsequent delivery to mitochondria enables one to maintain the efficient synthesis of PE and CL in the IMM. The use of peroxisomally produced acetyl-CoA for the synthesis of FFA in the cytosol allows FFA to enter the biosynthetic pathways for phospholipids and neutral lipids in the ER. See the text for additional details. Abbreviations: Ac-CoA, acetyl-CoA; ADHAP, acyl dihydroxyacetone phosphate; CDP-DAG, cytidine diphosphate-diacylglycerol; CL, cardiolipin; EE, ergosteryl esters; FA-CoA, fatty acid-CoA; FFA, non-esterified (free) fatty acids; LPA, lysophosphatidic acid; MLCL, monolysocardiolipin; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine; TAG, triacylglycerols; WT, wild-type.

Figure 2

A mechanism through which lithocholic acid (LCA) prolongs the longevity of chronologically aging yeast. Exogenously added LCA enters a yeast cell, where it is sorted to mitochondria, but not to any other organelle. Mitochondria-associated LCA is located predominantly in the inner mitochondrial membrane (IMM) and also resides in the outer mitochondrial membrane (OMM). LCA drives a remodeling of the mitochondrial membrane lipidome, thereby enlarging mitochondria, reducing their number and causing a build-up within their matrix of cristae disconnected from the IMM. These major changes in mitochondrial abundance and morphology elevate mitochondrial respiration, membrane potential, ATP synthesis and reactive oxygen species (ROS) levels in chronologically “old” cells, thereby enhancing their long-term stress resistance and viability. Moreover, the LCA-elicited remodeling of the mitochondrial membrane lipidome mitigates mitochondrial fragmentation, thus slowing down an age-related form of apoptotic programmed cell death. All of these distinctive alterations in vital mitochondrial processes and features seen in yeast cells permanently exposed to exogenous LCA extend their chronological lifespan. See the text for additional details. Abbreviations: CDP-DAG, cytidine diphosphate-diacylglycerol; CL, cardiolipin; ER, endoplasmic reticulum; ETC, electron transport chain; MLCL, monolysocardiolipin; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine; ΔΨ, electrochemical membrane potential.

Figure 3

A mechanism underlying an anti-tumor effect of lithocholic acid (LCA) in cultured human neuroblastoma cells. LCA is the most potent natural agonist of TGR5, a plasma membrane-bound G protein-coupled receptor. LCA binding to TGR5 on the cell surface compromises viability and/or proliferation of human neuroblastoma cells by triggering three different pathways. The first pathway is initiated when LCA-stimulated TGR5 activates the cAMP/PKA signaling cascade. The ensuing specific changes in mitochondrial redox processes and morphology cause an activation of mitochondrial outer membrane permeabilization (MOMP), thus triggering the intrinsic (mitochondrial) pathway of apoptotic death. The second pathway leads to activation of the initiator caspase-8. Activated caspase-8 cleaves and stimulates both the executioner caspase-3 and BID (BH3-interacting domain death agonist), thus eliciting both the extrinsic (death receptor) and intrinsic (mitochondrial) pathways of apoptotic death, respectively. The third pathway operates via an inhibition of the inflammatory caspase-1, thus slowing down the processing and secretion of the cytokines interleukin-1β and interleukin-18 and, ultimately, attenuating the growth and proliferation of neighboring neuroblastoma cells. See the text for additional details. Abbreviations: Csp-1, -3, -6, -8 and -9, caspases-1, -3, -6, -8 and -9.