Role of CHOP in Hepatic Apoptosis in the Murine Model of Intragastric Ethanol Feeding

Abstract

CHOP null (-/-) mice have remarkable absence of hepatocellular apoptosis in response to alcohol feeding but no protection against hyperhomocysteinemia, ER stress, and fatty liver. Thus, CHOP up-regulation occurs downstream of and contributes to one manifestation of ER stress, namely, apoptosis. Microarray studies confirmed by PCR analysis and western blotting indicate that genes affected by CHOP are both proapoptotic and antiapoptotic and CHOP induction by ethanol may tip the balance of cell survival and death toward apoptosis.

The role of fatty acids in the development and progression of nonalcoholic fatty liver disease

“…The induction of ER stress was mediated, in part, by hyperhomocysteinemia, and was independent of TNF-α. In a subsequent study by the same group, CHOP null mice were protected against ethanol-induced apoptosis despite the development of fatty liver, suggesting a causal role for this transcription factor in alcohol-related cell death [90].…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Chop deletion protects mice from various hepatocyte-specific challenges, including bile duct ligation (Tamaki et al 2008), acetaminophen (Uzi et al 2013), alcohol feeding (Ji et al 2005), and diet-induced steatohepatitis (Rinella et al 2011;Toriguchi et al 2014). In contrast to the beneficial effect of Chop deficiency, Chop −/− mice fed a methionine-choline-deficient (MCD) diet display increased liver damage (Soon et al 2010), possibly explained by a net accumulation of activated macrophages due to decreased death in the absence of CHOP (Malhi et al 2013).…”

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

“…10,11 In particular, CHOP deficiency attenuates cell death induced by alcohol or cholestasis in the liver. 12,13 Various lines of evidence, includ-ing the re-expression of fetal IGF-II, and overexpression of IGF-I, IGF-1R and its downstream signaling molecules indicate that the IGF-1R pathway is activated in liver disease. 14 -17 Indeed, IGF-1R may control regeneration, 18 fibrogenesis 15,19 and carcinogenesis 20 in the liver.…”