Ethanol and signal transduction in the liver

Hoek, Jan B.; Thomas, Andrew P.; Rooney, Thomas; Higashi, Katsuyoshi; Rubin, Emanuel

doi:10.1096/fasebj.6.7.1563591

Cited by 149 publications

(88 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is in line with and extends previous reports on the effect of ethanol on the activation of several protein kinases, such as PKC, JNK, and p42/44 MAPK, that are involved in different signal transduction pathways. 61,62 Because of the complexity of alterations induced by ethanol and DDC intoxication, one must take into account that besides the cytokeratin IFs, a variety of other cellular proteins are affected as well and thus could contribute to the observed cytoskeletal changes.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Stumptner¹,

Omary²,

Fickert³

et al. 2000

The American Journal of Pathology

View full text Add to dashboard Cite

Alcoholic hepatitis (AH) is associated with cytokeratin 8 and 18 (CK8/18) accumulation as cytoplasmic inclusion bodies , termed Mallory bodies (MBs).Cytokeratins are members of the large family of intermediate filament (IF) cytoskeletal proteins, which are normally expressed in a tissue-specific manner and assembled as cytoplasmic filamentous arrays. Neurofilaments, ␣-internexin, desmin, vimentin, glial filaments, and the nuclear lamins 1,2 also belong to the IF family. The diverse cell biological functions of IFs are still poorly understood. However, a diversity of human diseases is associated with severe alterations of IFs. A common pathological feature of many IF-related diseases is the accumulation of intracytoplasmic inclusions consisting of modified IF proteins, for example in neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Lewy body dementia 3-6 ; in neuromuscular disorders (eg, spheroid body myositis 7 ); and the formation of Mallory bodies (MBs) in alcoholic hepatitis (AH) and other liver disorders (eg, non-alcoholic steatohepatitis, Wilson's disease, primary biliary cirrhosis, Indian childhood cirrhosis, hepatocellular neoplasms 8 -11 ). Although the underlying pathogenetic mechanisms are as yet unclear, posttranslational modifications of IF proteins, such as phosphorylation, limited proteolysis, and crosslinking, may play a major role. For example, the presence of hyperphosphorylated neurofilament epitopes in some neuronal inclusion bodies 12-15 and of abnormally phosphorylated desmin in muscle fibers 16 were reported. Furthermore, a possible association of cytokeratin hyperphosphorylation with the formation of MBs in hepatocytes, a hallmark of AH, was suggested by in vitro and animal studies performed by our own group and others. [17][18][19][20] AH follows chronic alcohol abuse and occurs in 20 to 40% of heavy drinkers. Although reversible at the beginning, most cases of AH progress to irreversible cirrhosis. Besides the amount of alcohol ingested per day, a variety of other factors such as dietary habits, genetic factors influencing alcohol metabolism, viral infections, and additional toxins or drugs seem to determine the extent of liver damage. Classical morphological features of AH are liver cell ballooning and necrosis, inflammation, steatosis, and the formation of cytokeratin-containing MBs, which is associated with severe derangement (ie, diminution or even loss) of the hepatocyte cytokeratin IF network. 8 -11,22-26 Diverse animal models have been generated to study in more detail and under defined conditions mechanisms involved in the pathogenesis of this alcoholic liver disease. Experimental long-term intoxication of mice with Supported by the grants of the Austrian Science Foundation S7401-MOB (to K. Z.) and 7628-MED (to H. D.) and by a U.S. Veterans Affairs Merit and Career Development Award (to M. B. O.).

show abstract

Section: Discussionmentioning

confidence: 99%

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Stumptner¹,

Omary²,

Fickert³

et al. 2000

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…[7][8][9] Ethanol has previously been shown to modulate numerous signaling pathways, including those linked through phospholipase C, adenylyl cyclase (AC), protein kinase C, and tyrosine kinase-linked receptors in both hepatocytes and other cell types. [10][11][12] Furthermore, the adaptive alterations of guanine nucleotide regulatory proteins (G-proteins) reported in regenerating liver are further modulated following chronic ethanol exposure. 13,14 These data have led us to postulate that G-proteins are key factors in the mediation of ethanol-induced changes in hepatocyte and HCC mitogenesis.…”

mentioning

confidence: 99%

Enhanced Gi–Protein-Mediated Mitogenesis Following Chronic Ethanol Exposure in A Rat Model of Experimental Hepatocellular Carcinoma

et al. 1999

View full text Add to dashboard Cite

Cirrhosis caused by chronic ethanol abuse remains a common clinical precursor to the development of hepatocellular carcinoma (HCC). 1,2 However, while clinical and epidemiological evidence linking alcohol abuse to HCC is compelling, mechanistic evidence directly linking chronic alcohol consumption to HCC development and/or progression in humans remains poor as a result of superimposed factors precluding unequivocal conclusions from being drawn. 2 This problem is in part a result of the inability to generate chronic ethanol-induced models of cirrhosis in vivo. 3 In addition, precise controls are difficult to produce because of the multiplicity of ethanol' s effects both on the liver and the organism as a whole. Previous reports have demonstrated that both chronic and acute exposure to ethanol act to alter normal hepatic functions, including carbohydrate and lipid metabolism, as well as protein and DNA synthesis. 4,5 Ethanol has been reported to affect the proliferation in hepatocytes in vitro and in vivo.

show abstract

“…Ethanol administered acutely and chronically is known to interfere with polyphosphoinositide signalling pathways [2,3]. The acute administration of ethanol is known to disorder or fluidize membranes.…”

Section: Introductionmentioning

confidence: 99%

“…In intact hepatocytes, ethanol and other short-chain alcohols activated the polyphosphoinositide-specific phospholipase C and initiated the polyphosphoinositide signal transduction cascade [2,3]. In permeabilized hepatocytes (under conditions in which hormonal stimulation was abolished), ethanol was ineffective in activating G-protein-mediated phospholipase Cβ [7].…”

Section: Introductionmentioning

confidence: 99%

Activity of phosphatidylinositol transfer protein is sensitive to ethanol and membrane curvature

Komatsu

Bouma

Wirtz

et al. 2000

Biochemical Journal

View full text Add to dashboard Cite

Phosphatidylinositol transfer protein (PITP) is critical for many cellular signalling and trafficking events that are influenced by ethanol. The influence of ethanol and membrane curvature on the activity of recombinant mouse PITP-α in vitro is evaluated by monitoring the transfer of phosphatidylinositol (PtdIns) from rat hepatic microsomes to unilamellar vesicles. Acute exposure to pharmacological levels of ethanol enhanced the function of PITP. Chloroform shared a similar ability to enhance function when both drug concentrations were normalized to their respective octanol/water partition coefficients, indicating that the effect is not unique to ethanol and might be common to hydrophobic solutes. Neither the PITP activity nor its ethanol enhancement was altered by using thermally pretreated (denatured) or protease-treated microsomes, indicating that the native microsomal protein structure was unlikely to be a determinant of transfer. Kinetic analyses indicated that ethanol acted by increasing the PITP-mediated flux of PtdIns from both microsomal and liposomal surfaces. The activity of PITP was strongly dependent on the lipid structure, with a steep dependence on the expressed curvature of the membrane. Activity was greatest for small, highly curved sonicated vesicles and decreased markedly for large, locally planar unilamellar vesicles. Ethanol enhanced PITP-mediated PtdIns transfer to all vesicles, but its effect was much smaller than the enhancement due to curvature, which is consistent with ethanol's comparatively modest ability to perturb membrane lipids. The ethanol efficacy observed is as pronounced as any previously described lipid-mediated ethanol action. In addition, these observations raise the possibility that PITP specifically delivers PtdIns to metabolically active membrane domains of convex curvature and/or low surface densities of lipid.

show abstract

Ethanol and signal transduction in the liver

Cited by 149 publications

References 1 publication

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Hepatocyte Cytokeratins Are Hyperphosphorylated at Multiple Sites in Human Alcoholic Hepatitis and in a Mallory Body Mouse Model

Enhanced Gi–Protein-Mediated Mitogenesis Following Chronic Ethanol Exposure in A Rat Model of Experimental Hepatocellular Carcinoma

Activity of phosphatidylinositol transfer protein is sensitive to ethanol and membrane curvature

Contact Info

Product

Resources

About