IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

Axelle Cadoret^*, Colette Rey^*, Dominique Wendum^*, Khaldoun Elriz^*, François Tronche, Martin Holzenberger^* and Chantal Housset^*¶

From the INSERM,^* Centre de Recherche Saint-Antoine, UMR_S 938, Paris; the Université Pierre et Marie Curie (UPMC) Univ Paris 6, Centre de Recherche Saint-Antoine, UMR_S 938, Paris; the Assistance Publique-Hopitaux de Paris (AP-HP), Hôpital Saint-Antoine, Service d’Anatomie Pathologique, Paris; the Centre National de la Recherche Scientifique (CNRS) UMR7148, Collège de France, Paris; and the AP-HP,^¶ Hôpital Tenon, Service de Biochimie-Hormonologie, Paris, France

The insulin-like growth factor type 1 receptor (IGF-1R) controlsaging and cellular stress, both of which play major roles inliver disease. Stimulation of insulin-like growth factor signalingcan generate cell death in vitro. Here, we tested whether IGF-1Rcontributes to stress insult in the liver. Cholestatic liverinjury was induced by bile duct ligation in control and liver-specificIGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed lessbile duct ligation-induced hepatocyte damage than controls,while no differences in bile acid serum levels or better adaptationto cholestasis by efflux transporters were found. We thereforetested whether stress pathways contributed to this phenomenon;oxidative stress, ascertained by both malondialdehyde contentand heme oxygenase-1 expression, was similar in knockout andcontrol animals. However, together with a lower level of eukaryoticinitiation factor-2 ${alpha}$ phosphorylation, the endoplasmic reticulumstress protein CHOP and its downstream pro-apoptotic targetBax were induced to lesser extents in LIGFREKO mice than incontrols. Expression levels of cytokeratin 19, transforminggrowth factor-β1, ${alpha}$ -smooth muscle actin, and collagen ${alpha}$ 1(I)in LIGFREKO mice were all lower than in controls, indicatingreduced ductular and fibrogenic responses and increased cholestasistolerance in these mutants. This stress resistance phenotypewas also evidenced by longer post-bile duct ligation survivalin mutants than controls. These results indicate that IGF-1Rcontributes to cholestatic liver injury, and suggests the involvementof both CHOP and Bax in this process.