Metabolic derivatives of alcohol and the molecular culprits of fibro-hepatocarcinogenesis: Allies or enemies?

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 derivative	Mechanism/pathway	Cellular context	Ref.
Alcohol, LPS, SAMe	Inhibition of TGF-β/Smad signaling abrogates alcohol-induced liver injury	Cultured 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
AA	Up-regulation of Smad3 and Smad4, increase in nuclear translocation of Smad3/4 complex, decrease in Smad7 expression, all leading to enhanced expression of COL1A2	Human 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
Alcohol	Alcohol-induced increase in endotoxemia linked to up-regulated protein expression of TGF-β1, IL-6, NF-κB, TNF-α, IκBα	Guinea pig liver	[224]
Alcohol, LPS	Alcohol potentiates LPS-induced pancreatic fibrosis via increased production of TGF-β1	Human pancreatic tissue sample, pancreatic acinar-like cells (AR42J)	[225]
Alcohol	Alcohol-induced translocation of S. suis across gut wall and also up-regulated TGF-β1 and COL 1 to promote liver disease	Alcoholics, mice, Caco-2 cells	[59]
Alcohol	While 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 Smad2/3	Rat 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
Alcohol	Alcohol modulates iron-induced liver injury via increased expression of TGF-β1, BMP2, phosphorylated Smad2	Mice	[228]
Alcohol	Alcohol-induced steatosis and liver injury in Smad7 null mice is enhanced by TGF-β1 signaling and TGF-β1-induced EMT in hepatocytes	Alb-Cre mice, Smad7 (loxP/loxP) mice	[229]
Alcohol	Alcohol 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 signaling	Mice	[230]
Alcohol, AA	Alcohol and AA-induced activation of TGF-β1, JNK and p38 signaling pathways were inhibited by butein	HSCs, HepG2 cells	[231]
Alcohol	TGF-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 integrity	Rat HSCs	[232]
Alcohol, LPS	LPS and CYP2E1-dependent oxidative stress synergistically activate p38/JNK pathway via LPS/TNF-α signaling pathway	Hepatic cells	[233]
Alcohol	Alcohol induces cytotoxicity via activation of p38, JNK and ERK MARK pathway, but COS reversed this by inhibiting the MAPK pathway and activation of Nrf2	Human L02 normal liver cells	[234]
Alcohol	Alcohol induces hepatotoxicity by activating p38/JNK MAPK pathway in addition to NF-κB, IL-6, TNF-α, but these effects were reversed by MA	Mice	[235]
Alcohol	Activation 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-6	Adult male Balb/c mice, primary rat hepatocytes	[236]
Alcohol	TLR2/4, 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 factors	Mice	[237]
Alcohol	Alcohol-induced hepatocyte apoptosis is mediated through activation of p38/JNK MAPK pathway and also involve Fas	Human liver adenocarcinoma (SK-Hep1) cells	[238]
LPS	LPS induces liver inflammation via multiple pathways including activation of p38 MAPK/Nrf2/HO-1, ICAM-1, VCAM-1, TNF-α	RAW264.7 cells, CLP-induced septic mice	[239]
Alcohol	ERK MAPK activation, increase in mRNA transcripts of egr-1 and PAI-1 are associated with alcohol-induced steatosis and hepatic necrosis	Rats	[240]
LPS	Activation of p38 MAPK pathway and COX-2 mediate LPS-induced liver injury, however, ES attenuates liver injury by modulating the above pathways	Sprague-Dawley (SD) rats	[241]
Alcohol	Activation of p38, JNK and ERK MAPK pathways and histone modification (acetylation, methylation and phosphorylation) mediates alcohol-induced hepatic cellular injury	Male SD rats	[242]
Alcohol	Alcohol enhances Fas-induced liver injury by activating p38/JNK MAPK pathway, increase caspase-3 and -8 and TNF-α	Mice	[243]
LPS	Alcohol 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]
Alcohol	Inhibition of liver regeneration in partial hepatectomized rats is associated with alcohol-induced p38 activation and cyclin D1 expression	Male Wistar rats	[245]
Alcohol	Alcohol-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 stress	Human hepatocytes	[246]
Alcohol	Increased 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 gut	C57BL/6 mice, PAI-1-1-H/Kβ mice	[247]
Alcohol, LPS	Increase in PAI-1 correlated with progression of ALD	In 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

ALD: Alcoholic liver disease; HGF; Hepatocyte growth factor; ECM: Extracellular matrix; PAI: Plasminogen activator inhibitor; PI3K: Phosphatidylinositol 3-kinase; EGF: Epidermal growth factor; MAPK: Mitogen activated protein kinase; TGF-β: Transforming growth factor beta; Smad: Small mother against decapentaplegic; SAMe: S-adenosyl-L-methionine.