Dean J. Tuma

University of Nebraska Medical Center, Omaha, Nebraska, United States

Are you Dean J. Tuma?

Claim your profile

Publications (289)1294.98 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Chronic ethanol (EtOH) consumption decelerates the catabolism of long-lived proteins, indicating that it slows hepatic macroautophagy (hereafter called autophagy) a crucial lysosomal catabolic pathway in most eukaryotic cells. Autophagy and lysosome biogenesis are linked. Both are regulated by the transcription factor EB (TFEB). Here, we tested whether TFEB can be used as a singular indicator of autophagic activity, by quantifying its nuclear content in livers of mice subjected to acute and chronic EtOH administration. We correlated nuclear TFEB to specific indices of autophagy. Methods: In acute experiments, we gavaged GFP-LC3(tg) mice with a single dose of EtOH or with phosphate buffered saline (PBS). We fed mice chronically by feeding them control or EtOH liquid diets. Results: Compared with PBS-gavaged controls, livers of EtOH-gavaged mice exhibited greater autophagosome (AV) numbers, a higher incidence of AV-lysosome co-localization, and elevated levels of free GFP, all indicating enhanced autophagy, which correlated with a higher nuclear content of TFEB. Compared with pair-fed controls, livers of EtOH-fed mice exhibited higher AV numbers, but had lower lysosome numbers, lower AV-lysosome co-localization, higher P62/SQSTM1 levels, and lower free GFP levels. The latter findings correlated with lower nuclear TFEB levels in EtOH-fed mice. Thus, enhanced autophagy after acute EtOH gavage correlated with a higher nuclear TFEB content. Conversely, chronic EtOH feeding inhibited hepatic autophagy, associated with a lower nuclear TFEB content. Conclusions: Our findings suggest that the effect of acute EtOH gavage on hepatic autophagy differs significantly from that after chronic EtOH feeding. Each regimen distinctly affects TFEB localization, which in turn, regulates hepatic autophagy and lysosome biogenesis.
    Full-text · Article · Nov 2015 · Alcoholism Clinical and Experimental Research
  • C.A. Casey · D.J. Tuma · B.L. McVicker

    No preview · Article · Sep 2015

  • No preview · Article · Sep 2015 · Alcohol and Alcoholism

  • No preview · Article · Sep 2015 · Alcohol and Alcoholism
  • C. A. Casey · D. J. Tuma · B. L. McVicker

    No preview · Article · Sep 2015 · Alcohol and Alcoholism
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ethanol metabolism in the liver induces oxidative stress and altered cytokine production preceding fat accumulation in the liver. It is thought that there is a second hit that causes relatively benign fat accumulation to transform into liver failure. However, investigations into the mechanism(s) for this injury have been hampered by the lack of appropriate in vitro culture models in which to conduct in depth and specific studies. In order to overcome these shortcomings, we have developed the use of precision-cut liver slices (PCLSs) as an in vitro culture model in which to investigate how ethanol causes alcohol-induced liver injury. In this review, these studies will be discussed and some new data presented. Original investigations into the use of PCLS were obtained from chow fed male Wistar rats (200-300g), that were cultured up to 96h in media, 25 mM ethanol, or 25 mM ethanol and 0.5 mM 4-methylpyrazole (4-MP). Slices from multiple time points were examined for glutathione (GSH) levels, lipid peroxidation (TBARS assay), cytokine production (ELISA and RT-PCR) and myofibroblast activation (immunoblotting and immunohistochemistry for smooth muscle actin [SMA] and collagen). In other studies, age-matched male Sprague-Dawley rats were fed either high-fat (obese) (45% calories from fat, 4.73 kcal/g) or control diet for 13 months. PCLSs were prepared, incubated with 25 mM ethanol for various times, harvested, and evaluated for ethanol metabolism, triglyceride production, oxidative stress, and cytokine expression as outlined above. In newer experiments, human and mouse PCLSs were cut, equilibrated, and evaluated using the methods outlined above. In these studies, it was shown that the PCLSs from rats, mice and human livers retained excellent viability as determined by lactate dehydrogenase and ATP levels over a 96 hour period of incubation. More importantly, the major enzymes of ethanol detoxification; alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P4502E1, remained active and PCLSs readily metabolized ethanol and produced acetaldehyde. Within 24 hours and continuing up to 96 hours the PCLSs developed fatty livers and demonstrated an increase in the redox state. Treatment of PCLSs with 25 mM ethanol induced significant oxidative stress within 24h, including depletion of cellular GSH and increased lipid peroxidation compared to controls (P<0.05). Importantly, ethanol treatment accelerates the fibrogenic response after 48h, represented by significant increases in SMA and collagen 1α(I) production (P<0.05). Additionally, these ethanol-induced effects were prevented by the addition of 4-MP. In a separate study using obese rats, ethanol metabolism and acetaldehyde production decreased in PCLS compared to age-matched controls (AMC). While cytochrome P450 2E1 (CYP2E1) expression increased in response to ethanol, differences in PCLS from obese and control livers did not differ. Increased triglyceride production was observed in PCLS from obese rats compared to AMC, which further increased following ethanol incubation. Lipid peroxidation, measured by thiobarbituric acid reactive substances (TBARS) assay, increased in response to ethanol, while reduced glutathione (GSH) and heme oxygenase I (HO-1) levels were decreased. Tumor necrosis factor- alpha (TNF-α) and interleukin-6 (IL-6) levels were increased in the PCLS from obese rats, and increased further with ethanol incubation, while monocyte chemotactic protein-1 (MCP-1) expression decreased in ethanol challenged PCLS from obese rats. Ethanol metabolism induced oxidative stress (GSH depletion and increased lipid peroxidation) that results in fat accumulation in the liver. In addition, these phenomena precede and coincide with myofibroblast activation which occurs within 48h of treatment. Therefore, these findings support the concept that the development of fatty liver sensitizes the liver to the effects of ethanol and leads to the start of liver failure, necrosis and eventually cirrhosis. Thus, this model system appears to mimic the ethanol-induced changes in the liver that have been previously reported in human and animal studies, and may be a useful model for the study of alcoholic liver disease.
    No preview · Article · Aug 2015 · Current Molecular Pharmacology
  • Thomas P · Casey CA · Tuma DJ · McVicker BL

    No preview · Conference Paper · Aug 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol exposure worsens the course and outcomes of hepatitis C virus (HCV) infection. Activation of protective anti-viral genes is induced by interferon (IFN) α signaling, which is altered in liver cells by either HCV or ethanol exposure. However, the mechanisms of the combined effects of HCV and ethanol metabolism in IFNα signaling modulation are not well-elucidated. Here, we explored a possibility that ethanol metabolism potentiates HCV-mediated dysregulation of IFNα signaling in liver cells via impairment of methylation reactions. HCV-infected Huh7.5 CYP2E1(+) cells and human hepatocytes were exposed to acetaldehyde-generating system (AGS) and stimulated with IFNα to activate Interferon-Sensitive Genes (ISG) via the Jak-STAT1 pathway. We observed significant suppression of signaling events by acetaldehyde (Ach). Ach exposure decreased STAT1 methylation via activation of protein phosphatase 2A (PP2A) and increased the protein inhibitor of activated STAT1 (PIAS1)-STAT1 complex formation in both HCV+ and HCV- cells, preventing ISG activation. Treatment with a pro-methylating agent, betaine, attenuated all examined Ach-induced defects. Ethanol metabolism-induced changes in ISGs are methylation-related and confirmed by in vivo studies on HCV+Tg mice. HCV and Ach-induced impairment of IFN signaling temporaily increased HCV RNA levels followed by apoptosis of heavily infected cells. Ach potentiates the suppressive effects of HCV on activation of ISGs due to methylation-dependent dysregulation of IFNα signaling. A temporary increase in HCV RNA sensitizes the liver cells to Ach-induced apoptosis. Betaine reverses the inhibitory effects of Ach on IFN signaling and thus, can be used for treatment of HCV+ alcohol-abusing patients. Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology.
    Full-text · Article · Aug 2015 · AJP Gastrointestinal and Liver Physiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcoholic liver disease (ALD) is a major healthcare challenge worldwide. Emerging evidence reveals that ethanol administration disrupts the intestinal epithelial tight junction (TJ) complexes; this defect allows for the paracellular translocation of gut-derived pathogenic molecules to reach the liver to cause inflammation and progressive liver injury. We have previously demonstrated a causative role of impairments in liver transmethylation reactions in the pathogenesis of ALD. We have further shown that treatment with betaine, a methylation agent that normalizes liver methylation potential, can attenuate ethanol-induced liver injury. Herein, we explored whether alterations in methylation reactions play a causative role in disrupting intestinal mucosal barrier function by employing an intestinal epithelial cell line. Monolayers of Caco-2 cells were exposed to ethanol or a-pan methylation reaction inhibitor, tubercidin, in the presence and absence of betaine. The structural and functional integrity of intestinal epithelial barrier was then examined. We observed that exposure to either ethanol or tubercidin disrupted TJ integrity and function by decreasing the localization of TJ protein occludin-1 to the intracellular junctions, reducing transepithelial electrical resistance and increasing dextran influx. All these detrimental effects of ethanol and tubercidin were attenuated by co-treatment with betaine. We further show that the mechanism of betaine protection was through BHMT-mediated catalysis. Collectively, our data suggest a novel mechanism for alcohol-induced gut leakiness and identifies the importance of normal methylation reactions in maintaining TJ integrity. We also propose betaine as a potential therapeutic option for leaky gut in alcohol-consuming patients who are at the risk of developing ALD. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Biochemical pharmacology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Malondialdehyde-acetaldehyde (MAA) adducts are a product of oxidative stress associated with tolerance loss in several disease states. This study was undertaken to investigate the presence of MAA adducts and circulating anti-MAA antibodies in patients with rheumatoid arthritis (RA). Methods: Synovial tissue from patients with RA and patients with osteoarthritis (OA) were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA patients (n = 1,720) and healthy controls (n = 80) by enzyme-linked immunosorbent assay. Antigen-specific anti-citrullinated protein antibodies (ACPAs) were measured in RA patients using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of RA patients (n = 80) and matched healthy controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA positivity, were examined in all RA patients. Results: Expression of MAA adducts was increased in RA synovial tissue compared to OA synovial tissue, and colocalization with citrullinated proteins was found. Increased levels of anti-MAA antibody isotypes were observed in RA patients compared to controls (P < 0.001). Among RA patients, anti-MAA antibody isotypes were associated with seropositivity for ACPAs and rheumatoid factor (P < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a greater number of positive antigen-specific ACPA analytes (expressed at high titer) (P < 0.001) and a higher ACPA score (P < 0.001), independent of other covariates. Conclusion: MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPAs. These results support speculation that MAA formation may be a cofactor that drives tolerance loss, resulting in the autoimmune responses characteristic of RA.
    Full-text · Article · Mar 2015 · Arthritis and Rheumatology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We had previously shown that alcohol consumption can induce cellular isoaspartate protein damage via an impairment of the activity of protein isoaspartyl methyltransferase (PIMT), an enzyme that triggers repair of isoaspartate protein damage. To further investigate the mechanism of isoaspartate accumulation, hepatocytes cultured from control or 4-week ethanol-fed rats were incubated in vitro with tubercidin or adenosine. Both these agents, known to elevate intracellular S-adenosylhomocysteine levels, increased cellular isoaspartate damage over that recorded following ethanol consumption in vivo. Increased isoaspartate damage was attenuated by treatment with betaine. To characterize isoaspartate-damaged proteins that accumulate after ethanol administration, rat liver cytosolic proteins were methylated using exogenous PIMT and 3H-S-adenosylmethionine and proteins resolved by gel electrophoresis. Three major protein bands of ∼75-80 kDa, ∼95-100 kDa, and ∼155-160 kDa were identified by autoradiography. Column chromatography used to enrich isoaspartate-damaged proteins indicated that damaged proteins from ethanol-fed rats were similar to those that accrued in the livers of PIMT knockout (KO) mice. Carbamoyl phosphate synthase-1 (CPS-1) was partially purified and identified as the ∼160 kDa protein target of PIMT in ethanol-fed rats and in PIMT KO mice. Analysis of the liver proteome of 4-week ethanol-fed rats and PIMT KO mice demonstrated elevated cytosolic CPS-1 and betaine homocysteine S-methyltransferase-1 when compared to their respective controls, and a significant reduction of carbonic anhydrase-III (CA-III) evident only in ethanol-fed rats. Ethanol feeding of rats for 8 weeks resulted in a larger (∼2.3-fold) increase in CPS-1 levels compared to 4-week ethanol feeding indicating that CPS-1 accumulation correlated with the duration of ethanol consumption. Collectively, our results suggest that elevated isoaspartate and CPS-1, and reduced CA-III levels could serve as biomarkers of hepatocellular injury.
    Full-text · Article · Feb 2015 · Biochemical and Biophysical Research Communications
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is well established that alcohol consumption is related to the development of alcoholic liver disease. Additionally, it is appreciated that other major health issues are associated with alcohol abuse, including colorectal cancer (CRC) and its metastatic growth to the liver. Although a correlation exists between alcohol use and the development of diseases, the search continues for a better understanding of specific mechanisms. Concerning the role of alcohol in CRC liver metastases, recent research is aimed at characterizing the processing of carcinoembryonic antigen (CEA), a glycoprotein that is associated with and secreted by CRC cells. A positive correlation exists between serum CEA levels, liver metastasis, and alcohol consumption in CRC patients, although the mechanism is not understood. It is known that circulating CEA is processed primarily by the liver, first by nonparenchymal Kupffer cells (KCs) and secondarily, by hepatocytes via the asialoglycoprotein receptor (ASGPR). Since both KCs and hepatocytes are known to be significantly impacted by alcohol, it is hypothesized that alcohol-related effects to these liver cells will lead to altered CEA processing, including impaired asialo-CEA degradation, resulting in changes to the liver microenvironment and the metastatic potential of CRC cells. Also, it is predicted that CEA processing will affect cytokine production in the alcohol-injured liver, resulting in pro-metastatic changes such as enhanced adhesion molecule expression on the hepatic sinusoidal endothelium. This chapter examines the potential role that alcohol-induced liver cell impairments can have in the processing of CEA and associated mechanisms involved in CEA-related colorectal cancer liver metastasis.
    No preview · Article · Jan 2015 · Advances in Experimental Medicine and Biology
  • C.A. Casey · D. J. Tuma · B. L. McVicker

    No preview · Article · Nov 2014 · Alcohol
  • Source
    C A Casey · D J Tuma · B L McVicker
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol-induced alterations in cell function, hepatic inflammation, and fibrosis are prominent features of liver disease in general and of alcoholic liver injury in particular. The link between these processes, however, remains unclear. A virtually universal characteristic of liver injury and subsequent inflammation is the induction of hepatocellular damage, and work from our laboratory has extensively studied the effect of ethanol administration on the hepatocyte and the process of endocytosis by these cells, using the asialoglycoprotein receptor (ASGP-R) pathway as a model. Our recent studies have shown that impaired uptake of several ligands by the ASGP-R (cellular fibronectin, carcinoembryonic antigen, and apoptotic bodies) leads to an ethanol-induced accumulation which then contributes to enhanced activation and cytokine production by non-parenchymal cells such as Kupffer cells and liver endothelial cells. The interaction of these ligands with the sinusoidal cells of the liver, as well as the cooperation and regulation between the different cell types after ethanol administration warrants further investigation and is the focus of talk. In our work we aim to acquire a better understanding of the cross-interactive associations that occur between the cell types following chronic ethanol administration, and which contribute to inflammation.
    Preview · Article · Sep 2014 · Alcohol and alcoholism (Oxford, Oxfordshire). Supplement
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcoholic liver disease has been clinically well described, but the molecular mechanisms leading to hepatotoxicity have not been fully elucidated. Previously, we determined that microtubules are hyperacetylated and more stable in ethanol-treated WIF-B cells, VL-17A cells, liver slices, and in livers from ethanol-fed rats. From our recent studies, we believe that these modifications can explain alcohol-induced defects in microtubule motor-dependent protein trafficking including nuclear translocation of a subset of transcription factors. Since cytoplasmic dynein/dynactin is known to mediate both microtubule-dependent translocation and basolateral to apical/canalicular transcytosis, we predicted that transcytosis is impaired in ethanol-treated hepatic cells. We monitored transcytosis of three classes of newly synthesized canalicular proteins in polarized, hepatic WIF-B cells, an emerging model system for the study of liver disease. As predicted, canalicular delivery of all proteins tested was impaired in ethanol-treated cells. Unlike in control cells, transcytosing proteins were observed in discrete sub-canalicular puncta en route to the canalicular surface that aligned along acetylated microtubules. We further determined that the stalled transcytosing proteins colocalized with dynein/dynactin in treated cells. No changes in vesicle association were observed for either dynein or dynactin in ethanol-treated cells, but significantly enhanced dynein binding to microtubules was observed. From these results, we propose that enhanced dynein binding to microtubules in ethanol-treated cells leads to decreased motor processivity resulting in vesicle stalling and in impaired canalicular delivery. Our studies also importantly indicate that modulating cellular acetylation levels with clinically tolerated deacetylase agonists may be a novel therapeutic strategy for treating alcoholic liver disease.
    Full-text · Article · Aug 2014 · Molecular and Cellular Biochemistry
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that chronic ethanol intake lowers hepatocellular S-adenosylmethionine to S-adenosylhomocysteine ratio and significantly impairs many liver methylation reactions. One such reaction, catalyzed by guanidinoacetate methyltransferase (GAMT), is a major consumer of methyl groups and utilizes as much as 40% of the SAM-derived groups to convert guanidinoacetate (GAA) to creatine. The exposure to methyl-group consuming compounds has substantially increased over the past decade that puts additional stresses on the cellular methylation potential. The purpose of our study was to investigate whether increased ingestion of a methyl-group consumer (GAA) either alone or combined with ethanol intake, plays a role in the pathogenesis of liver injury. Adult male Wistar rats were pair-fed the Lieber DeCarli control or ethanol diet in the presence or absence of GAA for 2weeks. At the end of the feeding regimen, biochemical and histological analyses were conducted. We observed that 2weeks of GAA- or ethanol-alone treatment increases hepatic triglyceride accumulation by 4.5 and 7-fold, respectively as compared with the pair-fed controls. However, supplementing GAA in the ethanol diet produced panlobular macro- and micro-vesicular steatosis, a marked decrease in the methylation potential and a 28-fold increased triglyceride accumulation. These GAA-supplemented ethanol diet-fed rats displayed inflammatory changes and significantly increased liver toxicity compared to the other groups. In conclusion, increased methylation demand superimposed on chronic ethanol consumption causes more pronounced liver injury. Thus, alcoholic patients should be cautioned for increased dietary intake of methyl-group consuming compounds even for a short period of time.
    Full-text · Article · May 2014 · Experimental and Molecular Pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have previously shown that decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio generated in livers of alcohol-fed rats can impair the activities of many SAM-dependent methyltransferases. One such methyltransferase is guanidinoacetate methyltransferase (GAMT) that catalyzes the last step of creatine synthesis. As GAMT is the major utilizer of SAM, the purpose of the study was to examine the effects of ethanol (EtOH) on liver creatine levels and GAMT activity. Male Wistar rats were pair-fed the Lieber-DeCarli control and EtOH diet for 4 to 5 weeks. At the end of the feeding regimen, the liver, kidney, and blood were removed from these rats for subsequent biochemical analyses. We observed ~60% decrease in creatine levels in the livers from EtOH-fed rats as compared to controls. The reduction in creatine levels correlated with lower SAM:SAH ratio observed in the livers of the EtOH-fed rats. Further, in vitro experiments with cell-free system and hepatic cells revealed it is indeed elevated SAH and lower SAM:SAH ratio that directly impairs GAMT activity and significantly reduces creatine synthesis. EtOH intake also slightly decreases the hepatocellular uptake of the creatine precursor, guanidinoacetate (GAA), and the GAMT enzyme expression that could additionally contribute to reduced liver creatine synthesis. The consequences of impaired hepatic creatine synthesis by chronic EtOH consumption include (i) increased toxicity due to GAA accumulation in the liver; (ii) reduced protection due to lower creatine levels in the liver, and (iii) reduced circulating and cardiac creatine levels. Chronic EtOH consumption affects the hepatic creatine biosynthetic pathway leading to detrimental consequences not only in the liver but could also affect distal organs such as the heart that depend on a steady supply of creatine from the liver.
    Full-text · Article · Nov 2013 · Alcoholism Clinical and Experimental Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alcoholic liver disease is manifested by the presence of fatty liver, primarily due to accumulation of hepatocellular lipid droplets (LDs). The presence of membrane-trafficking proteins (e.g., Rab GTPases) with LDs indicates that LDs may be involved in trafficking pathways known to be altered in ethanol (EtOH) damaged hepatocytes. As these Rab GTPases are crucial regulators of protein trafficking, we examined the effect EtOH administration has on hepatic Rab protein content and association with LDs. Male Wistar rats were pair-fed Lieber-DeCarli diets for 5 to 8 weeks. Whole liver and isolated LD fractions were analyzed. Identification of LDs and associated Rab proteins was performed in frozen liver or paraffin-embedded sections followed by immunohistochemical analysis. Lipid accumulation was characterized by larger LD vacuoles and increased total triglyceride content in EtOH-fed rats. Rabs 1, 2, 3d, 5, 7, and 18 were analyzed in postnuclear supernatant (PNS) as well as LDs. All of the Rabs were found in the PNS, and Rabs 1, 2, 5, and 7 did not show alcohol-altered content, while Rab 3d content was reduced by over 80%, and Rab 18 also showed EtOH-induced reduction in content. Rab 3d was not found to associate with LDs, while all other Rabs were found in the LD fractions, and several showed an EtOH-related decrease (Rabs 2, 5, 7, 18). Immunohistochemical analysis revealed the enhanced content of a LD-associated protein, perilipin 2 (PLIN2) that was paralleled with an associated decrease of Rab 18 in EtOH-fed rat sections. Chronic EtOH feeding was associated with increased PLIN2 and altered Rab GTPase content in enriched LD fractions. Although mechanisms driving these changes are not established, further studies on intracellular protein trafficking and LD biology after alcohol administration will likely contribute to our understanding of fatty liver disease.
    No preview · Article · Oct 2013 · Alcoholism Clinical and Experimental Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: The consumption of alcohol is associated with many health issues including alcoholic liver disease (ALD). The natural history of ALD involves the development of steatosis, inflammation (steatohepatitis), fibrosis and cirrhosis. During the stage of steatohepatitis, the combination of inflammation and cellular damage can progress to a severe condition termed alcoholic hepatitis (AH). Unfortunately, the pathogenesis of AH remains uncharacterized. Some modulations have been identified in host defense and liver immunity mechanisms during AH that highlight the role of intrahepatic lymphocyte accumulation and associated inflammatory cytokine responses. Also, it is hypothesized that alcohol-induced injury to liver cells may significantly contribute to the aberrant lymphocytic distribution that is seen in AH. In particular, the regulation of lymphocytes by hepatocytes may be disrupted in the alcoholic liver resulting in altered immunologic homeostasis and perpetuation of disease. In recent studies, it was demonstrated that the direct killing of activated T lymphocytes by hepatocytes is facilitated by the asialoglycoprotein receptor (ASGPR). The ASGPR is a well-characterized glycoprotein receptor that is exclusively expressed by hepatocytes. This hepatic receptor is known for its role in the clearance of desialylated glycoproteins or cells, yet neither its physiological function nor its role in disease states has been determined. Interestingly, alcohol markedly impairs ASGPR function; however, the effect alcohol has on ASGPR-mediated cytotoxicity of lymphocytes remains to be elucidated. This review discusses the contribution of hepatocytes in immunological regulation and, importantly, how pathological effects of ethanol disrupt hepatocellular-mediated defense mechanisms.
    No preview · Article · Sep 2013 · Hepatology International

  • No preview · Article · Aug 2013 · Alcohol and Alcoholism

Publication Stats

7k Citations
1,294.98 Total Impact Points


  • 1973-2015
    • University of Nebraska Medical Center
      • • Department of Internal Medicine
      • • Division of Gastroenterology and Hepatology (GI)
      • • Department of Biochemistry
      • • Division of Cardiology
      Omaha, Nebraska, United States
    • University of Nebraska at Omaha
      • Department of Internal Medicine
      Omaha, Nebraska, United States
  • 2004-2011
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 1992-2005
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 1997-2001
    • Creighton University
      • Department of Chemistry
      Omaha, Nebraska, United States
  • 1980-1992
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1978
    • Rutgers New Jersey Medical School
      Newark, New Jersey, United States