Browsing by Subject "liver injury"

Now showing 1 - 5 of 5
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    The Activation and Function of Autophagy in Alcoholic Liver Disease
    (Bentham Science Publishers, 2017) Khambu, Bilon; Wang, Lin; Zhang, Hao; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
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    Diverse Consequences in Liver Injury in Mice with Different Autophagy Functional Status Treated with Alcohol
    (Elsevier, 2019) Yan, Shengmin; Zhou, Jun; Chen, Xiaoyun; Dong, Zheng; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Alcoholic fatty liver disease is often complicated by other pathologic insults, such as viral infection or high-fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high-fat diet, or viral infection, which in turn affects the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined after acute binge or chronic-plus-binge treatment. Mice given alcohol with either mode and induced with deficiency in liver-specific autophagy-related protein (Atg)-7 shortly after the induction of Atg7 deletion had elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7–deficient mice, in which Atg7 was deleted in embryos, were more susceptible with chronic-plus-binge but not with acute alcohol treatment. Constitutive hepatic Atg5–deficient mice, in which Atg5 was deleted in embryos, were more susceptible with acute alcohol treatment, but liver injury was unexpectedly improved with the chronic-plus-binge regimen. A prolonged Atg deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regimen.
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    Ethanol-triggered Lipophagy Requires SQSTM1 in AML12 Hepatic Cells
    (Nature Publishing group, 2017-08-26) Wang, Lin; Zhou, Jun; Yan, Shengmin; Lei, Guangsheng; Lee, Chao-Hung; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Ethanol-induced hepatic lipophagy plays an important cytoprotective role against liver injury, but its mechanism is not fully determined. In the present study, ethanol-induced lipophagy was studied in an immortalized mouse hepatocyte line, AML12. We found that ethanol treatment elevated lipid content in these cells, which could be regulated by autophagy. To determine the potential mechanism, we investigated the role of a key adaptor molecule SQSTM1/p62. SQSTM1 can bind to LC3 on autophagosomes and ubiquitinated molecules on cargos, thus facilitating the autophagic engulfment of the cargo. We found that both LC3 and SQSTM1 could colocalize with lipid droplets (LDs) following ethanol treatment. Colocalization of LC3 with LDs was significantly inhibited by SQSTM1 knockdown, which also reduced ethanol-induced lipid elevation. In addition, increased ubiquitin signals were found to colocalize with SQSTM1 on LDs in response to ethanol. Moreover, the SQSTM1 signal was colocalized with that of perilipin1, a major protein on LDs. Finally, perilipin1 knockdown significantly altered ethanol-induced lipophagy. Taken together, these data support a model in which autophagosomes were directed to the LDs via SQSTM1, which bound to ubiquitinated proteins, possibly including perilipin 1, on LDs. This study provides a potential mechanistic explanation to how ethanol induces lipophagy in hepatocytes.
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    Fructose Promotion of Intestinal and Liver Injury: A Sugar by Any Other Name That Isn't So Sweet
    (Wiley, 2019) Kennedy, Lindsey; Francis, Heather; Alpini, Gianfranco; Medicine, School of Medicine
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    Nrf2 Deficiency Augments the Activity of Hepatic Progenitor Cells during Cholestasis
    (Office of the Vice Chancellor for Research, 2013-04-05) Wang, Guo-Ying; Zou, Yuhong; Dai, Guoli
    Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular defense against oxidative stress and inflammation and is also involved in regulating liver regeneration. The aim of the study is to evaluate whether Nrf2 mediates hepatic repair response during cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation or sham operation. Various assessments were performed at 5, 10, 15, 25, and 40 days following surgery. Significant genotype-dependent differences in liver injury, cell proliferation, and collagen deposition were not seen over the time course of the study, in line with several reports. However, Nrf2-null mice exhibited a more prominent network of septual tissue containing laminin and α-fetal protein expressing cells at 15 days after injury, suggesting a stronger repair response, than their wild-type litter mates. In the livers of both genotypes of mice, cytokeratin 19 (CK19), a marker of bipotent liver epithelial progenitors and immature billiary epithelial cells, were expressed in the epithelial cells of newly formed bile ducts and a population of hepatocytic-appearing cells in parenchyma. Notably, Nrf2-null mice showed higher hepatic protein expression of CK19 at 5 days following BDL, indicating earlier onset of the activation of CK19+ progenitor cells, than wild-types. CD133, a marker of liver progenitors, were found to be expressed by newly generated bile duct epithelial cells and a population of hepatocytic-appearing parenchymal cells in the livers of the two genotypes of mice. Hepatic CD133 protein expression was gradually elevated, paralleling continuous increase in the number of CD133+ hepatocytic-appearing cells, as the cholestasis progressed. Remarkably, the lack of Nrf2 led to markedly higher magnitudes of the increases in hepatic CD133 protein level and in the number of CD133+ hepatocytic-appearing cells. Collectively, our data demonstrate that Nrf2 deficiency evokes higher activity of liver progenitor cells and thus stronger liver repair response. The findings indicate that Nrf2 is an important regulator of the activity of hepatic progenitor/stem cells during chronic liver injury.