| 1 | Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis显示文摘Background:Liver regeneration following partial hepatectomy(PHx)is a complicated process involving multiple organs and several types of signaling networks.The bile acid-activated metabolic pathways occupy an auxiliary yet important chapter in the entire biochemical story.PHx is characterized by rapid but transient bile acid overload in the liver,which constitutes the first wave of proliferative signaling in the remnant hepatocytes.Bile acids trigger hepatocyte proliferation through activation of several nuclear receptors.Following biliary passage into the intestines,enterocytes reabsorb the bile acids,which results in the activation of farnesoid X receptor(FXR),the consequent excretion of fibroblast growth factor(FGF)19/FGF15,and its release into the enterohepatic circulation.FGF19/FGF15 subsequently binds to its cognate receptor,fibroblast growth factor receptor 4(FGFR4)complexed withβ-klotho,on the hepatocyte membrane,which initiates the second wave of proliferative signaling.Because some bile acids are toxic,the remnant hepatocytes must resolve the potentially detrimental state of bile acid excess.Therefore,the hepatocytes orchestrate a bile acid detoxification and elimination response as a protective mechanism in concurrence with the proliferative signaling.The response in part results in the excretion of(biotransformed)bile acids into the canalicular system,causing the bile acids to end up in the intestines.Relevance for patients:Recently,FXR agonists have been shown to promote regeneration via the gut-liver axis.This type of pharmacological intervention may prove beneficial for patients with hepatobiliary tumors undergoing PHx.In light of these developments,the review provides an in-depth account of the pathways that underlie post-PHx liver regeneration in the context of bile acid homeostasis in the liver and the gut-liver signaling axis. | Lianne de Haan Sarah Jvan der Lely Anne-Loes K.Warps Quincy Hofsink Pim B.Olthof Mark J.de Keijzer Daniel A.Lionarons Lionel Mendes-Dias Bote G.Bruinsma Korkut Uygun Hartmut Jaeschke Geoffrey C.Farrell Narci Teoh Rowan Fvan Golen Tiangang Li Michal Heger | 2018 | Journal of Clinical & Translational Research2018，4，1： | 2 |
| 2 | Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-κB or Akt/mTORC1显示文摘Background:There are strong links between obesity,diabetes and hepatocellular carcinoma(HCC),but molecular mechanisms remain unclear.Aim:We tested the proposed involvement of NF-κB,IL-6/STAT3 and Akt/mTORC1 before onset(at 3 months)and at onset(6 months)of accelerated hepatocarcinogenesis in DEN-injected obese and diabetic foz/foz compared to lean wildtype(Wt)mice,and also studied the hepatocyte proliferative response to DNA damage between the obese and lean lines.Methods:Male foz/foz and Wt littermates fed normal chow were DEN-injected(10mg/kg i.p.)at age 12-15 days.To test the effect of mTOR inhibitor on growth of dysplastic hepatocytes,a separate cohort of DEN-injected foz/foz mice was administered rapamycin(4 mg/kg body weight/day).Results:foz/foz mice developed obesity,hyperinsulinemia,diabetes,adipokine dysregulation and fatty liver,without increased serum or liver TNF-αor serum IL-6.All DEN-injected foz/foz mice developed HCC by 6 mths vs.0/10 lean Wt.At 3 mths,there were more dysplastic hepatocytes in DEN-injected foz/foz than Wt,with increased liver injury(serum ALT),hepatocyte apoptosis(M30-positive cells)and proliferation(cyclin D1,cyclin E,PCNA),but neither NF-κB nor STAT3 activation.foz/foz livers exhibited upregulation of DNA damage sensors ATM and ATR,with inadequate cell cycle checkpoint controls(CHK1,CHK2,p53,p21).Akt and mTORC1 were highly activated in livers from foz/foz vs.Wt mice.Despite such activation,rapamycin failed to reduce growth of dysplastic hepatocytes.Conclusions:Accelerated DEN-induced HCC in obese/diabetic mice is linked to enhanced growth of dysplastic hepatocytes that cannot be attributed to NF-κB or IL-6/STAT3 activation,nor to sustained mTORC1 activation.The critical mechanism for obesity-enhanced hepatocarcinogenesis lies in the disconnection between hepatocellular injury with DNA damage,and an unrestrained proliferative response.Relevance for patients:This study supports the epidemiological data linking obesity,diabetes and fatty liver disease with increased risk for developing HCC.The findings also suggest that mTORC1 inhibition may not be beneficial in the prevention of obesity-related hepatocarcinogenesis. | Evi Arfianti Claire Z Larter Seungsoo Lee Vanessa Barn Geoffrey Haigh Matthew M.Yeh George NIoannou Narci C.Teoh Geoffrey C.Farrell | 2016 | Journal of Clinical & Translational Research2016，2，1： | 1 |
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