Hélène Gilgenkrantz

Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease

The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis, represents the main type of hepatocyte death in chronic cholestasis. Moreover, it has also been suggested that the reduced liver injury observed in the absence of Fas receptor after bile duct ligation was not due to lower hepatocyte apoptosis but to the indirect role of this receptor in non-hepatocytic cells such as cholangiocytes and inflammatory cells. The aim of this work was therefore to determine whether a protection against cell death limited to hepatocytes could be sufficient to reduce liver injury and delay cholestatic fibrosis. With this purpose, we performed bile duct ligation in transgenic mice overexpressing Bcl-2 in hepatocytes and in wild-type littermates. We found that, compared with necrosis, apoptosis was negligible in this model. Our results also showed that hepatocyte Bcl-2 expression protected hepatocytes against liver injury only in the early steps of the disease. This protection was correlated with reduced mitochondrial dysfunction and lipid peroxidation. However, in contrast to Fas receptor-deficient lpr mice, fibrosis progression was not hampered and liver inflammatory response was not reduced by Bcl-2 overexpression. These results therefore comfort the hypothesis that Fas-mediated apoptotic hepatocyte pathway is not a significant contributing factor to the clinical features observed in cholestasis. Moreover, in the absence of a blunted inflammatory response in transgenic mice, Bcl-2 protection against hepatocyte mitochondrial dysfunction and lipid peroxidation was not sufficient to block fibrosis progression.

Rodent Models of Liver Repopulation

The liver has an extraordinary faculty to regenerate. Hepatocytes are highly differentiated cells that, despite a resting G0 state in the normal quiescent liver, can re-enter the cell cycle to reconstitute the organ after an injury. However, the first cell therapy approaches trying to harness this specific characteristic of the hepatocytes came up against the competition with resident hepatocytes in the ability to proliferate. This review will describe the different rodent models that have been developed in the last 15 years to demonstrate the concept of liver repopulation with transplanted cells harbouring a selective advantage over resident hepatocytes. Examples will then be given to show how these models demonstrated the therapeutic efficiency of cell transplantation in specific disorders. The transplantation of human hepatocytes into some of these mouse models led to the creation of humanized livers. These humanized mice provide a powerful tool to study the physiopathology of human hepatotropic pathogens and to develop drugs against them. Finally, emphasis will be placed on the role of these rodent models in the demonstration of the hepatocytic potential of stem cells.

Bile acids and FGF receptors: orchestrators of optimal liver regeneration

Because it fosters our dreams of immortality, regeneration has been for centuries a matter of fascination for countless biologists and clinicians. While in mammals regeneration is obviously less spectacular than in hydra, newt or zebrafish, it allows, in any case, repairing intestine, skin or liver. The latter organ is seen as a paradigmatic regeneration model because, as for an amputated fins zebrafish or newts forelimb, it is indeed possible to follow the complete restoration of a rodent liver mass after a 2/3 partial hepatectomy (PH) within a few days. The caveat is that most of our knowledge about liver regeneration is based on this specific surgical model. The amazing conclusion is that liver regeneration relies mainly on highly differentiated hepatocytes, which, while actively dividing to restore the missing part, maintain their vital functions.1 Hepatocytes are in a quiescent state (G0) in a normal adult liver. Following 2/3 PH, >95% of these parenchymal cells present in the remnant lobes divide in a rather synchronous manner, for one or two rounds of cell division. Other liver cell types, such as macrophages, cholangiocytes or endothelial cells, will divide afterwards. Schematically, one can distinguish two successive main steps allowing proper regeneration. The first phase requires the secretion of cytokines such as tumour necrosis factor-α and interleukin-6 in the very first minutes after PH, which poise hepatocytes to enter G1 phase and to become receptive to growth factors. The second step involves concomitantly metabolic changes, consisting in particular in a transient accumulation of lipid droplets, and in the activation of two growth factor pathways, epidermal growth factor receptor and c-Met. Both pathways then recruit scaffolding proteins and activate multiple intracellular intertwined networks, such as mitogen-activated protein kinases, signal transducer and activator of transcription 3 (STAT3), …

L’autophagie dans les maladies chroniques du foie - Un ami qui vous veut (presque) toujours du bien !

Within recycling damaged cell components, autophagy maintains cell homeostasis. Thus, it has been anticipated that autophagy would play an essential role in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most prevalent chronic liver diseases in Western countries, sharing common histopathologic features and a common disease progression. In this review, we discuss the role of autophagy at different stages of NAFLD and ALD as well as in liver regeneration and hepatocarcinogenesis.

Pre-therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness

Patients with severe alcoholic hepatitis (SAH) not responding to glucocorticoid therapy have higher mortality, though they do not differ in their baseline clinical characteristics and prognostic scores from those who respond to therapy. We hypothesized that the baseline hepatic gene expression differs between responders (R) and non-responders (NR). Baseline liver transcriptome was compared between R and NR in Indian (16 each) and French (5 NR, 3 R) patients with SAH. There were differentially expressed genes (DEGs) between NR and R, in Indian (1106 over-expressed, 96 under-expressed genes) and French patients (65 over-expressed, 142 under-expressed genes). Indian NR had features of hepatocyte senescence and French NR exhibited under-expression of genes involved in cell division, indicating a central defect in the capacity of hepatocytes for self-renewal in both populations. Markers of hepatic progenitor cell proliferation were either very few (Indian patients) or absent (French patients). No DEGs were enriched in inflammatory pathways and there were no differences in nuclear receptor subfamily 3 group C member 1 (NR3C1) transcript expression and splicing between NR and R. Our results reveal that baseline hepatic transcriptome is reflective of subsequent glucocorticoid non-response and indicate impaired regenerative potential of the liver as an underlying phenomenon in NR.