Polycystic kidney features of the renal pathology in glycogen storage disease type I: possible evolution to renal neoplasia

International audienceGlycogen storage disease type I (GSDI) is a rare genetic pathology characterized by glucose-6 phosphatase (G6Pase) deficiency, translating in hypoglycemia during short fasts. Besides metabolic perturbations, GSDI patients develop long-term complications, especially chronic kidney disease (CKD). In GSDI patients, CKD is characterized by an accumulation of glycogen and lipids in kidneys, leading to a gradual decline in renal function. At a molecular level, the activation of the renin-angiotensin system is responsible for the development of renal fibrosis, eventually leading to renal failure. The same CKD phenotype was observed in a mouse model with a kidney-specific G6Pase deficiency (K.G6pc-/- mice). Furthermore, GSDI patients and mice develop frequently renal cysts at late stages of the nephropathy, classifying GSDI as a potential polycystic kidney disease (PKD). PKDs are genetic disorders characterized by multiple renal cyst formation, frequently caused by the loss of expression of polycystic kidney genes, such as PKD1/2 and PKHD1. Interestingly, these genes are deregulated in K.G6pc-/- kidneys, suggesting their possible role in GSDI cystogenesis. Finally, renal cysts are known to predispose to renal malignancy development. In addition, HNF1B loss is a malignancy prediction factor. Interestingly, Hnf1b expression was decreased in K.G6pc-/- kidneys. While a single case of renal cancer has been reported in a GSDI patient, a clear cell renal carcinoma was recently observed in one K.G6pc-/- mouse (out of 36 studied mice) at a later stage of the disease. This finding highlights the need to further analyze renal cyst development in GSDI patients in order to evaluate the possible associated risk of carcinogenesis, even if the risk might be limited

Hepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent.

International audienceBACKGROUND & AIMS: During chronic HCV infection, activation of fibrogenesis appears to be principally related to local inflammation. However, the direct role of hepatic HCV protein expression in fibrogenesis remains unknown. METHODS: We used transgenic mice expressing the full length HCV open reading frame exposed to a 'second hit' of the fibrogenic agent carbon tetrachloride (CCl(4)). Both acute and chronic liver injuries were induced in these mice by CCl(4) injections. Liver injury, expression of matrix re-modeling genes, reactive oxygen species (ROS), inflammation, hepatocyte proliferation, ductular reaction and hepatic progenitor cells (HPC) expansion were examined. RESULTS: After CCl(4) treatment, HCV transgenic mice exhibited enhanced liver fibrosis, significant changes in matrix re-modeling genes and increased ROS production compared to wild type littermates despite no differences in the degree of local inflammation. This increase was accompanied by a decrease in hepatocyte proliferation, which appeared to be due to delayed hepatocyte entry into the S phase. A prominent ductular reaction and hepatic progenitor cell compartment expansion were observed in transgenic animals. These observations closely mirror those previously made in HCV-infected individuals. CONCLUSIONS: Together, these results demonstrate that expression of the HCV proteins in hepatocytes contributes to the development of hepatic fibrosis in the presence of other fibrogenic agents. In the presence of CCl(4), HCV transgenic mice display an intra-hepatic re-organization of several key cellular actors in the fibrogenic process

Dietary exacerbation of metabolic stress leads to accelerated hepatic carcinogenesis in glycogen storage disease type Ia

International audienceBACKGROUND & AIMS:Glycogen storage disease type Ia (GSDIa) is a rare genetic disease associated with glycogen accumulation in hepatocytes and steatosis. With age, most adult patients with GSDIa develop hepatocellular adenomas (HCA), which can progress to hepatocellular carcinomas (HCC). In this study, we characterized metabolic reprogramming and cellular defense alterations during tumorigenesis in the liver of hepatocyte-specific G6pc deficient (L.G6pc-/-) mice, which develop all the hepatic hallmarks of GSDIa.METHODS:Liver metabolism and cellular defenses were assessed at pretumoral (four months) and tumoral (nine months) stages in L.G6pc-/- mice fed a high fat/high sucrose (HF/HS) diet.RESULTS:In response to HF/HS diet, hepatocarcinogenesis was highly accelerated since 85% of L.G6pc-/- mice developed multiple hepatic tumors after nine months, with 70% classified as HCA and 30% as HCC. Tumor development was associated with high expression of malignancy markers of HCC, i.e. alpha-fetoprotein, glypican 3 and β-catenin. In addition, L.G6pc-/- livers exhibited loss of tumor suppressors. Interestingly, L.G6pc-/- steatosis exhibited a low-inflammatory state and was less pronounced than in wild-type livers. This was associated with an absence of epithelial-mesenchymal transition and fibrosis, while HCA/HCC showed a partial epithelial-mesenchymal transition in the absence of TGF-β1 increase. In HCA/HCC, glycolysis was characterized by a marked expression of PK-M2, decreased mitochondrial OXPHOS and a decrease of pyruvate entry in the mitochondria, confirming a "Warburg-like" phenotype. These metabolic alterations led to a decrease in antioxidant defenses and autophagy and chronic endoplasmic reticulum stress in L.G6pc-/- livers and tumors. Interestingly, autophagy was reactivated in HCA/HCC.CONCLUSION:The metabolic remodeling in L.G6pc-/- liver generates a preneoplastic status and leads to a loss of cellular defenses and tumor suppressors that facilitates tumor development in GSDI.LAY SUMMARY:Glycogen storage disease type Ia (GSD1a) is a rare metabolic disease characterized by hypoglycemia, steatosis, excessive glycogen accumulation and tumor development in the liver. In this study, we have observed that GSDIa livers reprogram their metabolism in a similar way to cancer cells, which facilitates tumor formation and progression, in the absence of hepatic fibrosis. Moreover, hepatic burden due to overload of glycogen and lipids in the cells leads to a decrease in cellular defenses, such as autophagy, which could further promote tumorigenesis in the case of GSDI

Hepatobiliary MR contrast agent uptake as a predictive biomarker of aggressive features on pathology and reduced recurrence-free survival in resectable hepatocellular carcinoma: comparison with dual-tracer 18F-FDG and 18F-FCH PET/CT

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ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

International audienceErythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice, genetically invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating b-catenin signaling increased binding of Tcf4/b-catenin complex and upregulated its enhancer function. The loss of Arid1a together with b-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis

Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury

International audienceBackground & Aims: Hepatic ischemia-reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia/reperfusion injuryMethods: We measured the activity of 9 small-molecule inhibitors of cyclophilins in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif–/– (CypD knockout) mice and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemia/reperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion and collected samples of blood and liver for histologic analysis.Results: The compounds inhibited peptidyl-prolyl isomerase activity (half maximal inhibitory concentration values, 0.2–16.2 μmol/L) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration values, 1.4–132 μmol/L) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif–/– mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia/reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle.Conclusions:Recently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria from mouse and human liver tissues. Administration of these compounds to mice during ischemia/reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage. These compounds might be developed to protect patients from ischemia/reperfusion injury after liver surgery or for other hepatic or nonhepatic disorders related to abnormal mPTP opening

Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury

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ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma

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