Alcohol feeding for 2, 4, or 8 weeks did not affect aldehyde dehy

Alcohol feeding for 2, 4, or 8 weeks did not affect aldehyde dehydrogenase 2 protein levels, but caused lower aldehyde dehydrogenase activity at 8 weeks. Alda-1 administration after acute alcohol

intoxication elevated hepatic aldehyde dehydrogenase 2 activity and accelerated acetaldehyde clearance. Alda-1 treatment for 10 days in the 8-week alcohol feeding model alleviated liver damage along with reduction of hepatic aldehydes. Alda-1 reactivated transcription factors, up-regulated fatty acid oxidation enzymes, and reversed steatosis. Alcohol-induced endoplasmic reticulum stress and apoptotic cell death were also attenuated by alda-1. Acetaldehyde or 4-hydroxynonenal Talazoparib research buy treatment of H4IIEC3 cells inactivated transcription factors and induced endoplasmic reticulum stress and apoptosis.

In summary, pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reversed alcohol exposure-induced hepatic steatosis and apoptosis by accelerating aldehyde clearance. This study indicates that aldehyde dehydrogenase 2 is a promising molecular target for alcoholic liver disease. Disclosures: The following people have nothing find more to disclose: Wei Zhong, Wenliang Zhang, Qiong Li, Guoxiang Xie, Qian Sun, Xiuhua Sun, Xiaobing Tan, Xinguo Sun, Zhanxiang Zhou Purpose: Alcohol consumption can cause alcoholic liver disease (ALD), which is a major cause of morbidity and mortality in the United States. Chronic alcohol consumption causes a pro-oxidant environment in the liver and increases hepatic lipid peroxidation. Acrolein (ACR) is the most reactive and toxic learn more aldehyde generated through

lipid peroxidation. ACR is also found in fried fatty foods and is a major component of cigarette smoke, which, in turn, negatively impacts chronic liver diseases. ACR forms protein adducts and triggers endoplasmic reticulum (ER) stress and hepatocyte apoptosis, which are recognized as etiologic factors in ALD. Emerging evidence has established the critical role of the gut-liver axis in ALD patho-genesis, wherein alcohol-induced gut barrier dysfunction leads to endotoxemia and contributes to liver injury. This study investigates the pathogenic role of acrolein as a major mediator of intestinal barrier dysfunction and hepatic ER stress and injury in ALD. Methods: We examined intestinal and hepatic effects of ACR and alcohol using in vitro (human intestinal epithelial Caco2 and rat hepatic H4IIEC cells) and in vivo (C57Bl/6 mice – chronic+binge (NIAAA) alcohol feeding) models. Accumulation of ACR adducts was detected by immunostaining. The effects of alcohol and ACR were assessed on (i) steatosis; (ii) injury/apoptosis; (iii) activation of the stress activated protein kinase, JNK; (iv) ER stress and levels of ATF3, ATF4, chaperones GRP78, GRP94,and pro-apoptotic CHOP; and (v) levels of intestinal tight junction proteins (ZO-1, occludin, and claudin), and intestinal barrier dysfunction.

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