title: 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.
authors.affiliation: Jinyao Liu, Department of Legal Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D000077261:Carvedilol; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011412:Propanolamines / Q000627:therapeutic use; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002227:Carbazoles; D018836:Inflammation Mediators; D011412:Propanolamines; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077261:Carvedilol; D000431:Ethanol
keywords: Alcohol; Alcoholic liver disease; Bone marrow-derived cell; Fatty liver; Hepatic stellate cell; Tumor necrosis factor-α