Alcohol-induced steatosis in liver cells.
Alcohol-induced fatty liver (steatosis) was believed to result from excessive generation of reducing equivalents from ethanol metabolism, thereby enhancing fat accumulation. Recent findings have revealed a more complex picture in which ethanol oxidation is still required, but specific transcription as well as humoral factors also have important roles. Transcription factors involved include the sterol regulatory element binding protein 1 (SREBP-1) which is activated to induce genes that regulate lipid biosynthesis. Conversely, ethanol consumption causes a general down-regulation of lipid (fatty acid) oxidation, a reflection of inactivation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) that regulates genes involved in fatty acid oxidation. A third transcription factor is the early growth response-1 (Egr-1), which is strongly induced prior to the onset of steatosis. The activities of all these factors are governed by that of the principal regulatory enzyme, AMP kinase. Important humoral factors, including adiponectin, and tumor necrosis factor-alpha (TNF-alpha), also regulate alcohol-induced steatosis. Their levels are affected by alcohol consumption and by each other. This review will summarize the actions of these proteins in ethanol-elicited fatty liver. Because steatosis is now regarded as a significant risk factor for advanced liver pathology, an understanding of the molecular mechanisms in its etiology is essential for development of effective therapies.
Donohue
Terrence M
TM
Liver Study Unit, Research Service (151), VA Medical Center, 4101 Woolworth Ave, Omaha, NE 68105, USA. tdonohue@unmc.edu
D000428:Alcohol Drinking / Q000503:physiopathology; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D047493:PPAR alpha / Q000502:physiology; D012307:Risk Factors; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology
D047493:PPAR alpha; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D000431:Ethanol