García-Villafranca Javier, Guillén Alberto, Castro José
Departamento de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense, Ciudad Universitaria, s/n, Madrid, Spain.
Biochimie. 2008 Mar;90(3):460-6. doi: 10.1016/j.biochi.2007.09.019. Epub 2007 Oct 5.
The mechanisms by which ethanol consumption causes accumulation of hepatic triacylglycerols are complex. AMP-activated protein kinase (AMPK) plays a central role in the regulation of lipid metabolism. Therefore, in the present study we investigated whether AMPK may have a role in the development of ethanol-induced fatty liver. Hepatocytes isolated from rats fed with an ethanol-containing liquid diet showed higher rates of fatty acid and triacylglycerol syntheses, but a decreased rate of fatty acid oxidation, concomitant to a lower activity of carnitine palmitoyltransferase I. Hepatocytes from both ethanol-fed and pair-fed control rats were incubated with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator in intact cells. In both hepatocyte preparations AICAR strongly inhibited the activity of acetyl-CoA carboxylase in parallel to fatty acid synthesis, but cells from ethanol-fed rats showed significantly lower sensitivity to inhibition by AICAR. Moreover, AICAR strongly decreased triacylglycerol synthesis and increased fatty acid oxidation in control hepatocytes, but these effects were markedly attenuated in hepatocytes from ethanol-fed rats. In parallel, AMPK in liver of ethanol-fed rats showed a decreased specific activity and a lower sensitivity to changes in the AMP/ATP ratio, compared to the enzyme of control rats. These effects are consistent with the impairment of AMPK-mediated regulation of fatty acid metabolism after ethanol consumption, that will facilitate triacylglycerol accumulation. Taken together, these findings suggest that a decreased AMPK activity may have an important role in the development of alcoholic fatty liver.
乙醇摄入导致肝脏三酰甘油蓄积的机制很复杂。AMP激活的蛋白激酶（AMPK）在脂质代谢调节中起核心作用。因此，在本研究中，我们调查了AMPK是否在乙醇诱导的脂肪肝发展中起作用。从喂食含乙醇液体饲料的大鼠分离的肝细胞显示出较高的脂肪酸和三酰甘油合成速率，但脂肪酸氧化速率降低，同时肉碱棕榈酰转移酶I的活性较低。将乙醇喂养和配对喂养的对照大鼠的肝细胞与5-氨基咪唑-4-甲酰胺核糖核苷（AICAR）一起孵育，AICAR是完整细胞中的AMPK激活剂。在两种肝细胞制剂中，AICAR均强烈抑制乙酰辅酶A羧化酶的活性，同时抑制脂肪酸合成，但乙醇喂养大鼠的细胞对AICAR抑制的敏感性明显较低。此外，AICAR强烈降低对照肝细胞中的三酰甘油合成并增加脂肪酸氧化，但在乙醇喂养大鼠的肝细胞中这些作用明显减弱。同时，与对照大鼠的酶相比，乙醇喂养大鼠肝脏中的AMPK显示出比活性降低和对AMP/ATP比值变化的敏感性降低。这些效应与乙醇摄入后AMPK介导的脂肪酸代谢调节受损一致，这将促进三酰甘油的蓄积。综上所述，这些发现表明AMPK活性降低可能在酒精性脂肪肝的发展中起重要作用。
