Many new mechanisms for alcoholic steatosis have been suggested by work reported in the last five years. These include alterations of transcriptional controls of lipid metabolism, better understanding of the effects of abnormal methionine metabolism on the endoplasmic reticulum stress response, unraveling of the basis for sensitization of the Kupffer cell to lipopolysaccharide, a better understanding of the role of cytokines and adipokines in alcoholic liver disease, and implication of the innate immune and complement systems in responses to alcohol. Much of this work has been facilitated by work with knockout mice. Undoubtedly, there are interrelationships among these various pathogenic mechanisms that ultimately will provide a more cohesive picture of how heavy alcohol use deranges hepatic lipid metabolism.

Hepatic steatosis is now understood to play an important role in the development of advanced liver disease. Alcoholic and nonalcoholic fatty liver each begin with the accumulation of lipids in the liver. Lipid accumulation in the liver can occur through maladaptations of fatty acid uptake (either through dietary sources or from fat tissue), fatty acid synthesis, fatty acid oxidation, or export of lipids from the liver. Alterations in mechanisms of fatty acid uptake through both dietary uptake and lipolysis in adipose tissue can contribute to the pathogenesis of both disorders, as can effects on fatty acid transporters. Effects on lipid synthesis in alcoholic and nonalcoholic fatty liver involve the endoplasmic reticulum (ER) stress response, homocysteine metabolism pathway, and different transcription factors regulating genes in the lipid synthesis pathway. Fatty acid oxidation, through effects on AMP-activated protein kinase (AMPK), adiponectin, peroxisome proliferator-activated receptors (PPARs), and mitochondrial function is predominantly altered in alcoholic liver disease, although studies suggest that activation of this pathway may improve nonalcoholic fatty liver disease. Finally, changes in fatty acid export, through effects on apolipoprotein B and microsomal transport protein are seen in both diseases. Thus, the similarities and differences in the mechanism of fat accumulation in the liver in nonalcoholic and alcoholic liver disease are explored in detail.

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Ethanol treatment of cultured hepatoma cells and of mice inhibited the activity of AMP-activated protein kinase (AMPK). This study shows that the inhibitory effect of ethanol on AMPK phosphorylation is exerted through the inhibition of the phosphorylation of upstream kinases and the activation of protein phosphatase 2A (PP2A).Inhibition of AMPK phosphorylation by palmitate was attributed to ceramide-dependent PP2A activation. We hypothesized that the inhibitory effect of ethanol on AMPK phosphorylation was mediated partly through the generation of ceramide. The effect of ethanol and inhibitors of ceramide synthesis on AMPK phosphorylation, ceramide levels, and PP2A activity were assessed in rat hepatoma cells (H4IIEC3). The effect of ethanol on hepatic ceramide levels was also studied in C57BL/6J mice fed the Lieber-DeCarli diet. In H4IIEC3 cells, ceramide reduced AMPK phosphorylation when they were treated for between 4 and 12 h. The basal level of AMPK phosphorylation in hepatoma cells was increased with the treatment of ceramide synthase inhibitor, fumonisin B1. Ethanol treatment significantly increased cellular ceramide content and PP2A activity by approximately 18-23%, when the cells were treated with ethanol for between 4 and 12 h. These changes in intracellular ceramide concentrations and PP2A activity correlated with the time course over which ethanol inhibited AMPK phosphorylation. The activation of PP2A and inhibition of AMPK phosphorylation caused by ethanol was attenuated by fumonisin B1 and imipramine, an acid sphingomyelinase (SMase) inhibitor. There was a significant increase in the levels of ceramide and acid SMase mRNA in the livers of ethanol-fed mice compared with controls. We concluded that the effect of ethanol on AMPK appears to be mediated in part through increased cellular levels of ceramide and activation of PP2A.

Sozio MS, Lu C, Zeng Y, Liangpunsakul S, Crabb DW. Activated AMPK inhibits PPAR-␣ and PPAR-␥ transcriptional activity in hepatoma cells.