TGF-β enhances alcohol dependent hepatocyte damage via down-regulation of alcohol dehydrogenase I

被引：51

作者：

Ciuclan, Loredana ^{[1
]}

Ehnert, Sabrina ^{[2
]}

Ilkavets, Iryna ^{[1
]}

Weng, Hong-Lei ^{[1
]}

Gaitantzi, Haristi ^{[1
]}

Tsukamoto, Hidekazu ^{[3
]}

Ueberham, Elke ^{[4
]}

Meindl-Beinker, Nadja M. ^{[1
]}

Singer, Manfred V. ^{[1
]}

Breitkopf, Katja ^{[1
]}

Dooley, Steven ^{[1
]}

机构：

[1] Univ Heidelberg, Fac Med Mannheim, Med Clin, D-68167 Mannheim, Germany

[2] Tech Univ Munich, Klinikum Rechts Isar, TH Munich, Dept Traumatol, D-8000 Munich, Germany

[3] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA

[4] Univ Leipzig, Paul Flechsig Inst Brain Res, Dept Neuroanat, Leipzig, Germany

来源：

JOURNAL OF HEPATOLOGY | 2010年 / 52卷 / 03期

关键词：

TGF-beta; ALKs; Smad7; Hepatocytes; Liver fibrosis; Alcohol metabolism; Steatosis; Mouse model; HEPATIC STELLATE CELLS; GROWTH-FACTOR-BETA; LIVER-DISEASE; NONOXIDATIVE METABOLISM; ETHANOL; EXPRESSION; FIBROSIS; INJURY; FIBROGENESIS; CYTOKINE;

D O I：

10.1016/j.jhep.2009.12.003

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

Background & Aims: Adverse alcohol effects in the liver involve oxidative metabolism, fat deposition and release of fibrogenic mediators, including TGF-beta. The work presents an assessment of liver damaging cross-talk between ethanol and TGF-beta in hepatocytes. Methods: To investigate TGF-beta effects on hepatocytes, micro-array analyses were performed and validated by qRT-PCR, Western blot analysis and immunohistochemistry. The cellular state was determined by assessing lactate dehydrogenase, cellular glutathione, reactive oxygen species, lipid peroxidation and neutral lipid deposition. RNA interference was used for gene silencing in vitro. Results: TGF-beta is induced in mouse livers after chronic ethanol insult, enhances ethanol induced oxidative stress and toxicity towards cultured hepatocytes plus induces lipid-, oxidative stress metabolism- and fibrogenesis-gene expression signatures. Interestingly, TGF-beta down-regulates alcohol metabolizing enzyme Adh1 mRNA in cultured hepatocytes and liver tissue from TGF-beta transgenic mice via the ALK5/Smad2/3 signalling branch, with Smad7 as a potent negative regulator. ADH1 deficiency is a determining factor for the increased lipid accumulation and Cyp2E1 dependent toxicity in liver cells upon alcohol challenge. Further, ADH1 expression was decreased during liver damage in an intra-gastric ethanol infusion mouse model. Conclusion: In the presence of ethanol, TGF-beta displays pro-steatotic action in hepatocytes via decreasing ADHI expression. Low ADHI levels are correlated with enhanced hepatocyte damage upon chronic alcohol consumption by favoring secondary metabolic pathways. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

引用

页码：407 / 416

页数：10

共 36 条

[1]

AHREU JG, 2002, NAT CELL BIOL, V4, P599

[2]

Advances in alcoholic liver disease [J].

Arteel, G ;

Marsano, L ;

Mendez, C ;

Bentley, F ;

McClain, CJ .

BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY, 2003, 17 (04) :625-647

[3]

Increased plasma fatty acid ethyl ester levels following inhibition of oxidative metabolism of ethanol by 4-methylpyrazole treatment in human subjects [J].

Best, Catherine A. ;

Sarkola, Taisto ;

Eriksson, C. J. Peter ;

Cluette-Brown, Joanne E. ;

Laposata, Michael .

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2006, 30 (07) :1126-1131

[4]

Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice [J].

Bhopale, Kamlesh K. ;

Wu, Hai ;

Boor, Paul J. ;

Popov, Vsevolod L. ;

Ansari, G. A. S. ;

Kaphalia, Bhupendra S. .

ALCOHOL, 2006, 39 (03) :179-188

[5]

Acetaldehyde stimulates the activation of latent transforming growth factor-β1 and induces expression of the type II receptor of the cytokine in rat cultured hepatic stellate cells [J].

Chen, A .

BIOCHEMICAL JOURNAL, 2002, 368 :683-693

[6]

Chen WX, 2002, WORLD J GASTROENTERO, V8, P379

[7]

Modulation of transforming growth factor β response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts [J].

Dooley, S ;

Delvoux, B ;

Lahme, B ;

Mangasser-Stephan, K ;

Gressner, AM .

HEPATOLOGY, 2000, 31 (05) :1094-1106

[8]

Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage [J].

Dooley, Steven ;

Hamzavi, Jafar ;

Ciuclan, Loredana ;

Godoy, Patricio ;

Ilkavets, Iryna ;

Ehnert, Sabrina ;

Ueberham, Elke ;

Gebhardt, Rolf ;

Kanzler, Stephan ;

Geier, Andreas ;

Breitkopf, Katja ;

Weng, Honglei ;

Mertens, Peter R. .

GASTROENTEROLOGY, 2008, 135 (02) :642-659

[9]

Blood monocyte-derived neohepatocytes as in vitro test system for drug metabolism [J].

Ehnert, S. ;

Nussler, A. K. ;

Lehmann, A. ;

Dooley, S. .

DRUG METABOLISM AND DISPOSITION, 2008, 36 (09) :1922-1929

[10]

Zonated expression of cytokines in rat liver: Effect of chronic ethanol and the cytochrome P450 2E1 inhibitor, chlormethiazole [J].

Fang, C ;

Lindros, KO ;

Badger, TM ;

Ronis, MJJ ;

Ingelman-Sundberg, M .

HEPATOLOGY, 1998, 27 (05) :1304-1310

← 1 2 3 4 →