Abstract
Alcoholic liver disease is a significant contributor to global liver failure. In murine models, chronic ethanol consumption dysregulates PTEN/Akt signaling. Hepatospecific deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTENLKO) mice possess constitutive activation of Akt(s) and increased de novo lipogenesis resulting in increased hepatocellular steatosis. This makes PTENLKO a viable model to examine the effects of ethanol in an environment of preexisting steatosis. The aim of this study was to determine the impact of chronic ethanol consumption and the absence of PTEN (PTENLKO) compared to Alb-Cre control mice (PTENf/f) on hepatocellular damage as evidenced by changes in lipid accumulation, protein carbonylation and alanine amino transferase (ALT). In the control PTENf/f animals, ethanol significantly increased ALT, liver triglycerides and steatosis. In contrast, chronic ethanol consumption in PTENLKO mice decreased hepatocellular damage when compared to PTENLKO pair-fed controls. Consumption of ethanol elevated protein carbonylation in PTENf/f animals but had no effect in PTENLKO animals. In PTENLKO mice, overall hepatic mRNA expression of genes that contribute to GSH homeostasis as well as reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations were significantly elevated compared to respective PTENf/f counterparts. These data indicate that during conditions of constitutive Akt activation and steatosis, increased GSH homeostasis assists in mitigation of ethanol-dependent induction of oxidative stress and hepatocellular damage. Furthermore, data herein suggest a divergence in EtOH-induced hepatocellular damage and increases in steatosis due to polyunsaturated fatty acids downstream of PTEN.
Highlights
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two of the leading causes of liver disease in the United States today
Given that in the Western world, obesity and nonalcoholic steatohepatitis (NASH) are rapidly increasing it is critical to understand that combinatorial effects of alcohol and NASH
Recent research has clearly demonstrated that a major regulator of hepatocellular lipid accumulation is the Phosphatase and tensin homolog on chromosome 10 (PTEN)/Akt pathway [12]
Summary
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two of the leading causes of liver disease in the United States today Both ALD and NAFLD are characterized by progressive hepatocellular damage manifested in increased steatosis, steatohepatitis, fibrosis and progression to cirrhosis [1]. Moderate alcohol consumption by human subjects with increased body mass index is strongly correlated with increased hepatic damage as determined by plasma alanine amino transferase (ALT) and Gamma-Glutamyl Transferase levels [2]. Given these statistics, obesity and its concomitant steatosis are predictable cofactors for ALD
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