Browsing by Author "Yin, Xiao-Ming"

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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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    Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury
    (Springer Nature, 2019-09-12) Tang, Chengyuan; Han, Hailong; Liu, Zhiwen; Liu, Yuxue; Yin, Lijun; Cai, Juan; He, Liyu; Liu, Yu; Chen, Guochun; Zhang, Zhuohua; Yin, Xiao-Ming; Dong, Zheng; Pathology and Laboratory Medicine, School of Medicine
    Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia-reperfusion (IR)-induced injury in mice. Functionally, silencing Bnip3 by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo, Bnip3 knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that Bnip3 knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.
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    AMDE-1 is a dual function chemical for autophagy activation and inhibition
    (PLoS, 2015-04-20) Li, Min; Yang, Zuolong; Vollmer, Laura L.; Gao, Ying; Fu, Yuanyuan; Lui, Cui; Chen, Xiaoyun; Liu, Peiqing; Vogt, Andreas; Yin, Xiao-Ming; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.
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    Automated assessment of steatosis in murine fatty liver
    (PLOS, 2018-05-10) Sethunath, Deepak; Morusu, Siripriya; Tuceryan, Mihran; Cummings, Oscar W.; Zhang, Hao; Yin, Xiao-Ming; Vanderbeck, Scott; Chalasani, Naga; Gawrieh, Samer; Computer and Information Science, School of Science
    Although mice are commonly used to study different aspects of fatty liver disease, currently there are no validated fully automated methods to assess steatosis in mice. Accurate detection of macro- and microsteatosis in murine models of fatty liver disease is important in studying disease pathogenesis and detecting potential hepatotoxic signature during drug development. Further, precise quantification of macrosteatosis is essential for quantifying effects of therapies. Here, we develop and validate the performance of automated classifiers built using image processing and machine learning methods for detection of macro- and microsteatosis in murine fatty liver disease and study the correlation of automated quantification of macrosteatosis with expert pathologist’s semi-quantitative grades. The analysis is performed on digital images of 27 Hematoxylin & Eosin stained murine liver biopsy samples. An expert liver pathologist scored the amount of macrosteatosis and also annotated macro- and microsteatosis lesions on the biopsy images using a web-application. Using these annotations, supervised machine learning and image processing techniques, we created classifiers to detect macro- and microsteatosis. For macrosteatosis prediction, the model’s precision, sensitivity and area under the receiver operator characteristic (AUROC) were 94.2%, 95%, 99.1% respectively. When correlated with pathologist’s semi-quantitative grade of steatosis, the model fits with a coefficient of determination value of 0.905. For microsteatosis prediction, the model has precision, sensitivity and AUROC of 79.2%, 77%, 78.1% respectively. Validation by the expert pathologist of classifier’s predictions made on unseen images of biopsy samples showed 100% and 63% accuracy for macro- and microsteatosis, respectively. This novel work demonstrates that fully automated assessment of steatosis is feasible in murine liver biopsies images. Our classifier has excellent sensitivity and accuracy for detection of macrosteatosis in murine fatty liver disease.
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    Autophagy in Alcoholic Liver Disease, Self-eating Triggered by Drinking
    (Elsevier, 2015-09) Wang, Lin; Khambu, Bilon; Zhang, Hao; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Macroautophagy (autophagy) is an evolutionarily conserved mechanism. It is important for normal cellular function and also plays critical roles in the etiology and pathogenesis of a number of human diseases. In alcohol-induced liver disease, autophagy is a protective mechanism against the liver injury caused by alcohol. Autophagy is activated in acute ethanol treatment but could be suppressed in chronic and/or high dose treatment of alcohol. The selective removal of lipid droplets and/or damaged mitochondria is likely the major mode of autophagy in reducing liver injury. Understanding the dynamics of the autophagy process and the approach to modulate autophagy could help finding new ways to battle against alcohol-induced liver injury.
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    Autophagy in liver diseases: A matter of what to remove and whether to keep
    (KeAi Communications, 2018-09) Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
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    Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease
    (Elsevier, 2018-09) Khambu, Bilon; Yan, Shengmin; Huda, Nazmul; Liu, Gang; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis. Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases. Impaired autophagy prevents the clearance of excessive lipid droplets (LDs), damaged mitochondria, and toxic protein aggregates, which can be generated during the progression of various liver diseases, thus contributing to the development of steatosis, injury, steatohepatitis, fibrosis, and tumors. In this review, we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases. We also examine the mechanisms of defects in autophagy, and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), focusing mainly on steatosis and liver injury. Finally, we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.
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    Autophagy induced by calcium phosphate precipitates targets damaged endosomes
    (ASBMB, 2014-04-18) Chen, Xi; Khambu, Bilon; Zhang, Hao; Gao, Wentao; Li, Min; Chen, Xiaoyun; Yoshimori, Tamotsu; Yin, Xiao-Ming; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Calcium phosphate precipitates (CPPs) form complexes with DNA, which enter cells via endocytosis. Under this condition CPPs induce autophagy via the canonic autophagy machinery. Here we showed that CPP-induced autophagy was also dependent on endocytosis as the process was significantly inhibited by methyl-β-cyclodextrin and dynasore, which suppress clathrin-dependent endocytosis. Consistently, CPP treatment triggered the formation of filipin-positive intracellular vesicles whose membranes are rich in cholesterol. Unexpectedly, these vesicles were also positive for galectin 3, suggesting that they were damaged and the membrane glycans became accessible to galectins to bind. Endosome damage was caused by endocytosis of CPPs and was reversed by calcium chelators or by endocytosis inhibitors. Notably, CPP-induced LC3-positive autophagosomes were colocalized with galectin 3, ubiquitin, and p62/SQSTM1. Inhibition of galectin 3 reduced p62 puncta and autophagosome formation. Knockdown of p62 additionally inhibited the colocalization of autophagosomes with galectins. Furthermore, most of the galectin 3-positive vesicles were colocalized with Rab7 or LAMP1. Agents that affect endosome/lysosome maturation and function, such as bafilomycin A1, also significantly affected CPP-induced tubulovesicular autophagosome formation. These findings thus indicate that endocytosed CPPs caused endosome damage and recruitment of galectins, particularly at the later endosome stage, which led to the interaction of the autophagosomal membranes with the damaged endosome in the presence of p62.
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    Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap
    (Nature Research, 2018-11-23) Lee, Youngmin A.; Noon, Luke A.; Akat, Kemal M.; Ybanez, Maria D.; Lee, Ting-Fang; Berres, Marie-Luise; Fujiwara, Naoto; Goossens, Nicolas; Chou, Hsin-I; Parvin-Nejad, Fatemeh P.; Khambu, Bilon; Kramer, Elisabeth G.M.; Gordon, Ronald; Pfleger, Cathie; Germain, Doris; John, Gareth R.; Campbell, Kirk N.; Yue, Zhenyu; Yin, Xiao-Ming; Cuervo, Ana Maria; Czaja, Mark J.; Fiel, M. Isabel; Hoshida, Yujin; Friedman, Scott L.; Pathology and Laboratory Medicine, School of Medicine
    Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.
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    Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions
    (MDPI, 2019-10-11) Yan, Shengmin; Khambu, Bilon; Hong, Honghai; Liu, Gang; Huda, Nazmul; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.