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

Abstract

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-α activity. 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)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression 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-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease.

Keywords: Alcohol, Fatty liver, Tumor necrosis factor-α, Hepatic stellate cell, Bone marrow-derived cell, Alcoholic liver disease

Core tip: Alcohol induces fatty liver by increasing the nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide ratio; increasing the activity of sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1; and decreasing peroxisome proliferator-activated receptor-α activity in liver. Alcohol activates the innate immune system and induces an imbalance in the immune response followed by the activation of Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is responsible for the dysregulated SREBP-1 and PAI-1 activity. Bone marrow-derived cells and sympathetic hyperactivity-activated hepatic stellate cells are also responsible for TNF-α overproduction in ethanol-induced hepatosteatosis. Carvedilol may attenuate the progression of ethanol-induced hepatosteatosis by suppressing sympathetic activity.