Home Journals FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis

FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis

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Autophagy is a basic physiological response that enables cells to quickly react to stimuli threatening cellular homeostasis.2x[2]Galluzzi, L., Pietrocola, F., Levine, B., and Kroemer, G. Metabolic control of autophagy. Cell. 2014;
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Elevated hydrophobic bile acids, a hallmark of cholestatic liver diseases, lead to organelle stress and damage.4x[4]Woolbright, B.L. and Jaeschke, H. Novel insight into mechanisms of cholestatic liver injury. World J Gastroenterol. 2012;
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Here we report that in human cholestasis, a spectrum of mostly chronic liver diseases that cause elevated bile acids, autophagy is likely to be pathophysiologically impaired. In vitro data suggest that impairment of autophagy is due to FXR-dependent induction of Rubicon, an inhibitor of autophago-lysosomal maturation (Fig. 6). In line with our in vivo findings in cholestatic liver samples, cholestatic concentrations of CDCA, which is a natural FXR agonist ligand and the major retained bile acid during chronic cholestasis, as well as pharmacological concentrations of the selective FXR ligand OCA, impair autophagy in vitro. We did not observe effects on the mTOR kinase pathway and our autophagy flux experiments suggested blockage of autophagy downstream of the vesicle initiation and elongation process. LC3/LAMP1 co-staining experiments pointed to defective autophago-lysosomal fusion at the end of the autophagic road.15x[15]Shen, H.M. and Mizushima, N. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends Biochem Sci. 2014;
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Fig. 6

Summary of suggested events.

Normal: After autophagosome formation, mature double-membrane autophagosomes fuse with lysosomes (or as a step in between with endosomes) for final degradation as single-membrane autophagolysosomes. The fusion process (and more globally also endocytic trafficking) is positively controlled by the UVRAG complex and inhibited by the Rubicon complex. Cholestasis: Accumulating bile acids in cholestatic conditions or OCA as potent FXR agonist trans-activate FXR and increase Rubicon expression. Increased blocking by the Rubicon complex impairs fusion of autophagosomes with lysosomes/endosomes resulting in increased accumulation of autophagosomes and blocked execution of autophagic flux. UDCA treatment: UDCA treatment induces autophagosome formation by an unknown mechanism. Rubicon is reduced as a consequence of induced autophagosome formation resulting in increased formation of autophagolysosomes and execution of autophagic flux. Figure adapted from.37x[37]Matsunaga, K., Noda, T., and Yoshimori, T. Binding Rubicon to cross the Rubicon. Autophagy. 2009;
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We initially speculated that Rab7 might be involved in inhibition of autophago-lysosomal fusion, since bile acids, autophago-lysosomal fusion defects and Rab7 have been linked before.9x[9]Manley, S., Ni, H.M., Kong, B., Apte, U., Guo, G., and Ding, W.X. Suppression of autophagic flux by bile acids in hepatocytes. Toxicol Sci. 2014;
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Rubicon is also significantly overexpressed in patients with non-alcoholic fatty liver disease.31x[31]Tanaka, S., Hikita, H., Tatsumi, T., Sakamori, R., Nozaki, Y., Sakane, S. et al. Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology. 2016;
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Treatment options for cholestatic liver diseases are limited. UDCA is the baseline treatment for many cholestatic diseases and is effective in halting disease progression in up to 65% of patients with primary biliary cholangitis. The exact mode of action of UDCA is not known but potential contributions include choleretic effects, modulation of bile acid pool composition and anti-apoptotic properties.33x[33]Beuers, U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;
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OCA is a second-line option for patients with primary biliary cholangitis, who do not respond or tolerate UDCA.35x[35]Nevens, F., Andreone, P., Mazzella, G., Strasser, S.I., Bowlus, C., Invernizzi, P. et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;
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In summary, we provide evidence that impaired autophagic processing is a common feature in models of human cholestasis and therefore may represent a common novel drug target in cholestatic liver diseases. In fact, stimulation of autophagy with the mTOR inhibitor rapamycin reduces injury in bile duct-ligated mice.26x[26]Gao, L., Lv, G., Guo, X., Jing, Y., Han, Z., Zhang, S. et al. Activation of autophagy protects against cholestasis-induced hepatic injury. Cell Biosci. 2014;
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Abbreviations

CDCA, chenodeoxycholic acid; ChIP, chromatin-immunoprecipitation; ChIP-qPCR, ChIP-quantitative PCR; ChIP-Seq, ChIP-sequencing; FXR/NR1H4, farnesoid X receptor; GCDCA, glycochenodeoxycholic acid; mTOR, molecular target of rapamycin; NT, non-targeting control; OCA, obeticholic acid; OSTβ/SLC51B, organic solute transporter-β; RT-qPCR, quantitative reverse-transcription PCR; shFXR, FXR shRNA knockdown cells; TCDCA, taurochenodeoxycholic acid; TUDCA, tauro-UDCA; UDCA, ursodeoxycholic acid.

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