Extracellular signal-regulated kinases 1/2 suppression aggravates transforming growth factor-beta1 hepatotoxicity: a potential mechanism for liver injury in methionine-choline deficient-diet-fed mice

Abstract

Hepatocyte cell death is a characteristic indication in the development of non-alcoholic steatohepatitis (NASH); however, the underlying mechanism is still unclear. In this study, we examined the potential mechanism(s) involved in the development of liver injury using a methionine-choline deficient (MCD) diet feeding NASH model. Male C57BL6/J mice were fed MCD and methionine-choline sufficient (MCS) diet for two weeks before being killed. Our results showed that MCD diet feeding resulted in fatty liver and liver injury, evidenced by increased hepatic triglyceride (TG), plasma alanine aminotransferases and hepatic thiobarbituric acid reactive substances levels in MCD-fed mice. Furthermore, we found that MCD diet feeding caused remarkable suppression of hepatic extracellular signal-regulated kinases (ERK) 1/2 activation and increased transforming growth factor (TGF)-beta1 levels in plasma and the liver tissue. In vitro investigations showed that intracellular MEK/ERK1/2 activation status played a critical role in the determination of sensitivity of hepatocytes to TGF-beta1-induced cell death. HepG2 cells, otherwise resistant to TGF-beta1 killing due to high level of ERK1/2 activation, was sensitized by U0126, a specific MEK/ERK1/2 inhibitor, to TGF-beta1 cytotoxicity. H4IIEC3 cells, which have lower level of constitutive ERK1/2 activity, are sensitive to TGF-beta1-induced cell death. Lastly, we demonstrated that administration of epidermal growth factor, a strong ERK1/2 activator, to MCD-fed mice attenuated liver injury without affecting hepatic TG accumulation. Our findings demonstrated that hepatic ERK1/2 inactivation aggravates TGF-beta1-induced hepatotoxicity, which may contribute, at least in part, to the initiation of liver injury in NASH.

Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model

“…For the decrease in the phosphorylations of MEK1/2 and ERK1/2, our findings were consistent with a previous report conducted in a methionine-choline deficient (MCD) mice model [35]. The inhibition of MEK1/2/ERK1/2 and subsequent increased activity of transcription of AP-1 are responsible for hepatocyte sensitization to oxidative stress for cell death induction [35, 36]. Thus, the restoration of MEK1/2/ERK1/2 and inhibition of AP-1 activity by SAMC seem to be one of the important effects of SAMC when exerting its hepato-protective function during NAFLD.…”

“…Taken together, in this study, inhibition of the JNK/c-Jun phosphorylation by SAMC treatment not only attenuated the FFAs-induced insulin resistance, but also contributed to the reduction of necroinflammation during NAFLD. For the decrease in the phosphorylations of MEK1/2 and ERK1/2, our findings were consistent with a previous report conducted in a methionine-choline deficient (MCD) mice model [35]. The inhibition of MEK1/2/ERK1/2 and subsequent increased activity of transcription of AP-1 are responsible for hepatocyte sensitization to oxidative stress for cell death induction [35, 36].…”

Repression of the Nuclear Receptor Small Heterodimer Partner by Steatotic Drugs and in Advanced Nonalcoholic Fatty Liver Disease

“…ERK1/2 inhibition has already been reported in several models of NAFLD. For instance, mice on an MCD diet showed a remarkable suppression of hepatic ERK1/2 activation (Wang et al, 2010a). On the opposite side, an increase in the level of phosphorylated ERK1/2 improved liver steatosis (Aghazadeh and Yazdanparast, 2010).…”

Increased 4-Hydroxynonenal Formation Contributes to Obesity-Related Lipolytic Activation in Adipocytes

“…In adipocytes, 4-HNE activated p38, leading to increased COX-2 expression and inflammation [30]. In hepatocytes, 4-HNE suppressed ERK1/2 activation [31], whereas it activated ERK1/2 in endothelial cells [32]. Furthermore, 4-HNE-induced JNK activation contributed to cellular dysfunction and apoptosis in a variety of cell types [33].…”