Abstract
Chronic alcohol consumption causes alcohol-induced lipogenesis and promotes hepatic injury by preventing the oxidation of hepatocellular fatty acids through the suppression of the activation of AMP-activated protein kinase (AMPK). HIMH0021, an active flavonoid compound, which is a component of the Acer tegmentosum extract, has been shown to protect against liver damage caused by alcohol consumption. Therefore, in this study, we aimed to determine whether HIMH0021 could regulate alcoholic fatty liver and liver injury in mice. Oral administration of 10 days of Lieber-DeCarli ethanol plus a single binge of 30% ethanol (chronic-plus-binge model) induced steatosis and liver injury and inflammation in mice, which appears similar to the condition observed in human patients with alcohol-related diseases. HIMH0021, which was isolated from the active methanol extract of A. tegmentosum, inhibited alcohol-induced steatosis and attenuated the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during hepatocellular alcohol metabolism, both of which promote lipogenesis as well as liver inflammation. Treatment with HIMH0021 conferred protection against lipogenesis and liver injury, inhibited the expression of cytochrome P4502E1, and increased serum adiponectin levels in the mice subjected to chronic-plus-binge feeding. Furthermore, in hepatocytes, HIMH0021 activated fatty acid oxidation by activating pAMPK, which comprises pACC and CPT1a. These findings suggested that HIMH0021 could be used to target a TNFα-related pathway for treating patients with alcoholic hepatitis.
Highlights
Alcohol-related diseases can be divided into two main categories: alcohol dependence and alcohol abuse [1,2]
Alcohol dependence, which is known as alcoholism, is a common substance-abuse disorder, where the patients are at an increased risk for cirrhosis, gastrointestinal bleeding, pancreatitis, and a wide variety of cancers
Our results indicated that HIMH0021 inhibits alcohol-induced steatosis through the AMPK/ cpt1a signaling pathway and protection liver injury from alcohol consumption in vivo, suggesting that it might be an effective therapeutic molecule for use in the treatment of alcoholic liver diseases
Summary
Alcohol-related diseases can be divided into two main categories: alcohol dependence and alcohol abuse [1,2]. Alcohol dependence, which is known as alcoholism, is a common substance-abuse disorder, where the patients are at an increased risk for cirrhosis, gastrointestinal bleeding, pancreatitis, and a wide variety of cancers. Alcohol abuse is the second most common cause of cirrhosis in the United States after hepatitis. There are a few known causes of alcohol-related diseases, the mechanisms underlying alcoholic pathogenesis. Several risk factors play an important role in the pathogenesis of alcohol-related diseases, including inflammation, hormone, oxidative stress, genetics, and hepatic mechanism [3,4,5]. The initial stage of alcohol-related diseases involves the development of fatty liver (steatosis) and accumulation of triglycerides in hepatocytes, which is a reversible condition. If alcohol consumption is continued, steatosis can progress to a potentially pathological condition such as steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma, especially in the presence of other co-morbidity factors [6]
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