Chronic Ethanol Exposure Potentiates Lipopolysaccharide Liver Injury Despite Inhibiting Jun N-terminal Kinase and Caspase 3 Activation

Abstract

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNF␣ to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNF␣, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4 -5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-B and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.

New Role of Resistin in Lipopolysaccharide-Induced Liver Damage in Mice

“…Second, even when early stages of apoptotic signaling are not impaired, low cellular energy levels may prevent the completion of the apoptotic signaling cascade, resulting in secondary necrosis (sometimes coined "necroptosis"; Malhi et al, 2006). A similar imbalance between increases in apoptosis and necrosis was observed by Koteish et al (2002) in a model of enhanced LPS-induced liver damage caused by chronic ethanol exposure. In particular, the authors of that study found that ethanol enhances LPS-induced necrosis but blunts apoptosis (Fig.…”

CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction

“…LPS directly causes liver injury by mechanisms involving inflammatory cells such as Kupffer cells, and chemical mediators such as superoxide, nitric oxide, and tumor necrosis factor (TNFa) and other cytokines [31,81,91]. In addition, LPS potentiates liver damage induced by hepatotoxins including ethanol [10,19,30,46,59,84]. In experimental alcoholic liver disease, the combination of LPS and chronic ethanol produces hepatic necrosis and inflammation [30,46,59,84].…”

“…In addition, LPS potentiates liver damage induced by hepatotoxins including ethanol [10,19,30,46,59,84]. In experimental alcoholic liver disease, the combination of LPS and chronic ethanol produces hepatic necrosis and inflammation [30,46,59,84]. Ethanol alters gut microflora, the source of LPS, and ethanol increases the permeability of the gut, thus increasing the distribution of LPS from the gut into the portal circulation (endotoxemia).…”

Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- & down-regulation of genes by ethanol in hepatocytes

“…Thus changes in the expression of genes have been implicated in the development of alcoholic liver diseases (ALD). Genes that are involved in ethanol metabolism (Morimoto et al, 1993;Ronis et al, 1993;Deaciuc et al, 2004a,b) cell signaling (Mochly-Rosen et al, 1988;Gordon et al, 1986;Hong et al, 2002a,b) and apoptosis (Yacoub et al, 1995;Deaciuc et al, 1999;Deaciuc et al, 2002a,b;Koteish et al, 2002) are highly sensitive to alcohol. Micro-array studies have also shown profile of hepatic gene expressions induced by alcohol consumption (Tadic et al, 2002;Deaciuc et al, 2004a,b;French et al, 2005).…”