Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver

Alcoholic fatty liver disease(AFLD),a potentially pathologic condition,can progress to steatohepatitis,fibrosis,and cirrhosis,leading to an increased probability of hepatic failure and death.Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes;increasing hepatic sterol regulatory element-binding protein(SREBP)-1,plasminogen activator inhibitor(PAI)-1,and early growth response-1 activity;and decreasing hepatic peroxisome proliferator-activated receptor-αactivity.Alcohol activates the innate immune system and induces an imbalance of the immune response,which is followed by activated Kupffer cell-derived tumor necrosis factor(TNF)-αoverproduction,which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity.Alcohol abuse promotes the migration of bone marrowderived cells(BMDCs)to the liver and then reprograms TNF-αexpression from BMDCs.Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell(HSC)feedback loop that in turn activates the HSCs,resulting in HSC-derived TNF-αoverproduction.Carvedilol may block this feedback loop by suppressing sympathetic activity,which attenuates the progression of AFLD.Clinical studies evaluating com-bination therapy of carvedilol with a TNF-αinhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease.