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Copyright ©The Author(s) 2016.
World J Gastroenterol. Jan 7, 2016; 22(1): 50-71
Published online Jan 7, 2016. doi: 10.3748/wjg.v22.i1.50
Table 1 Involvement of Transforming growth factor-β, Smad, plasminogen activator inhibitor-1 and mitogen activated protein kinase signaling pathways in alcoholic liver disease and fibro-hepatocarcinogenesis
Alcohol/ metabolic derivativeMechanism/pathwayCellular contextRef.
Alcohol, LPS, SAMeInhibition of TGF-β/Smad signaling abrogates alcohol-induced liver injuryCultured HSCs, male rats[120,221]
alcohol and LPS induce liver fibrosis via activation of TGF-β signaling in a Smad3-dependent fashion and down-regulation of Smad7, but SAMe could abrogate it and also restore Smad7 expression
AAUp-regulation of Smad3 and Smad4, increase in nuclear translocation of Smad3/4 complex, decrease in Smad7 expression, all leading to enhanced expression of COL1A2Human and mouse HSCs[159,219,222,223]
Increase in TGF-β1 secretion and up-regulated expression of TβRII in HSCs was linked to AA
AA increased COLα1 expression in HSCs in a Smad3-dependent manner
AlcoholAlcohol-induced increase in endotoxemia linked to up-regulated protein expression of TGF-β1, IL-6, NF-κB, TNF-α, IκBαGuinea pig liver[224]
Alcohol, LPSAlcohol potentiates LPS-induced pancreatic fibrosis via increased production of TGF-β1Human pancreatic tissue sample, pancreatic acinar-like cells (AR42J)[225]
AlcoholAlcohol-induced translocation of S. suis across gut wall and also up-regulated TGF-β1 and COL 1 to promote liver diseaseAlcoholics, mice, Caco-2 cells[59]
AlcoholWhile alcohol exposure impairs nuclear import of growth hormone-induced STAT5B and IL-6-induced STAT3, it had no effect on TGF-β1-induced nuclear import of Smad2/3Rat liver, adult male C57BL/6J mice[11,184,226,227]
TGF-β1 mediates liver fibrosis in experimental rats in a Smad4-dependent fashion
Alcohol-induces hepatic iron overload leading to liver damage via modulation of hepcidin through BMP6/Smad4 signaling pathway
AlcoholAlcohol modulates iron-induced liver injury via increased expression of TGF-β1, BMP2, phosphorylated Smad2Mice[228]
AlcoholAlcohol-induced steatosis and liver injury in Smad7 null mice is enhanced by TGF-β1 signaling and TGF-β1-induced EMT in hepatocytesAlb-Cre mice, Smad7 (loxP/loxP) mice[229]
AlcoholAlcohol exposure induces TGF-β1 release and activation of TGF-β1-induced down-regulation of alcohol dehydrogenase 1 (ADH1) mRNA transcripts in part through TGF-β/ALK5/Smad2/3 signalingMice[230]
Alcohol, AAAlcohol and AA-induced activation of TGF-β1, JNK and p38 signaling pathways were inhibited by buteinHSCs, HepG2 cells[231]
AlcoholTGF-β1 mediates alcohol-induced activation of HSCs via activation of p38/JNK MAPK pathway and overexpression of HSC markers including α-SMA, procollagen1, betulin and betulinic acid can reverse these pathways to restore liver integrityRat HSCs[232]
Alcohol, LPSLPS and CYP2E1-dependent oxidative stress synergistically activate p38/JNK pathway via LPS/TNF-α signaling pathwayHepatic cells[233]
AlcoholAlcohol induces cytotoxicity via activation of p38, JNK and ERK MARK pathway, but COS reversed this by inhibiting the MAPK pathway and activation of Nrf2Human L02 normal liver cells[234]
AlcoholAlcohol induces hepatotoxicity by activating p38/JNK MAPK pathway in addition to NF-κB, IL-6, TNF-α, but these effects were reversed by MAMice[235]
AlcoholActivation of JNK and ERK MAPK pathway mediates alcohol-induced oxidative stress, but HO-1-derived CO reversed these effects by activating p38 MAPK pathway just as CORM-2, which suppressed TNF-α and IL-6Adult male Balb/c mice, primary rat hepatocytes[236]
AlcoholTLR2/4, p38/ERK MAPK pathway, IL-1β, TNF-α, COX-2 mediate alcohol-induced liver injury, but noni juice (NJ) effectively reverses alcohol-induced liver injury by modulating the above factorsMice[237]
AlcoholAlcohol-induced hepatocyte apoptosis is mediated through activation of p38/JNK MAPK pathway and also involve FasHuman liver adenocarcinoma (SK-Hep1) cells[238]
LPSLPS induces liver inflammation via multiple pathways including activation of p38 MAPK/Nrf2/HO-1, ICAM-1, VCAM-1, TNF-αRAW264.7 cells, CLP-induced septic mice[239]
AlcoholERK MAPK activation, increase in mRNA transcripts of egr-1 and PAI-1 are associated with alcohol-induced steatosis and hepatic necrosisRats[240]
LPSActivation of p38 MAPK pathway and COX-2 mediate LPS-induced liver injury, however, ES attenuates liver injury by modulating the above pathwaysSprague-Dawley (SD) rats[241]
AlcoholActivation of p38, JNK and ERK MAPK pathways and histone modification (acetylation, methylation and phosphorylation) mediates alcohol-induced hepatic cellular injuryMale SD rats[242]
AlcoholAlcohol enhances Fas-induced liver injury by activating p38/JNK MAPK pathway, increase caspase-3 and -8 and TNF-αMice[243]
LPSAlcohol induces CYP2E1 and LPS overproduction, and CYP2E1 sensitizes hepatocytes to LPS/TNF-α-dependent injury and this is mediated through activation of p38/JNK MAPK pathway[244]
AlcoholInhibition of liver regeneration in partial hepatectomized rats is associated with alcohol-induced p38 activation and cyclin D1 expressionMale Wistar rats[245]
AlcoholAlcohol-induced inhibition of HO-1 is mediated through blockade of p38/ERK MAPK-dependent nuclear import of Nrf2, but quercetin can reverse this blockade to restore hepatoprotection against alcohol-induced oxidative stressHuman hepatocytes[246]
AlcoholIncreased gastric mRNA transcripts was reported as a response to alcohol-dependent nosae on the gut wall, suggesting the protective role of PAI-1 in the gutC57BL/6 mice, PAI-1-1-H/Kβ mice[247]
Alcohol, LPSIncrease in PAI-1 correlated with progression of ALDIn vitro and in vivo models of ALD, mice[199-201]
PAI-1 was implicated in hepatic inflammation and fibrosis in a two-hit model of ALD involving alcohol and LPS
Alcohol-induced increased in hepatic lipids was linked to up-regulation of PAI-1, but this was reversed by metformin