Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes
Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes
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DOI：
10.1016/s0006-2952(01)00679-7
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发表时间：
2001-08-15
影响因子：
5.8
通讯作者：
Pégorier, JP
中科院分区：
文献类型：
--
作者：
Fulgencio, JP;Kohl, C;Pégorier, JP
在24小时饥饿大鼠新鲜孵育的肝细胞中研究了二甲双胍对脂肪酸和葡萄糖代谢的短期影响。无论使用何种浓度，二甲双胍（5或50 mM）对油酸或辛酸氧化速率（CO2+酸溶性产品）均无影响。同样，二甲双胍对油酸酯酯化（甘油三酯和磷脂合成）没有影响，无论肝细胞是从饥饿（低酯化率）还是进食大鼠（高酯化率）中分离的。相比之下，二甲双胍显著降低了乳酸/丙酮酸、丙氨酸、二羟基丙酮和半乳糖的葡萄糖生成速率。使用交叉图实验，结果表明二甲双胍对肝硬化发生的主要影响位于磷酸二羟丙酮形成的上游。增加二甲双胍暴露时间（24小时而不是1小时）导致参与葡萄糖和脂肪酸代谢的基因表达发生显著变化。事实上，当肝细胞在50至500 μ M二甲双胍存在下培养时，编码调节蛋白的基因的表达：脂肪酸氧化（肉毒碱棕榈酰转移酶I），生酮（线粒体羟甲基戊二酰辅酶A合酶），和胚胎发育（葡萄糖6-磷酸酶，磷酸烯醇丙酮酸羧激酶）降低30 - 60%，而编码参与糖酵解的调节蛋白（葡萄糖激酶和肝型丙酮酸激酶）的基因的表达增加了250%。总之，本研究表明二甲双胍可通过短期（代谢）和长期（基因）效应降低肝葡萄糖生成。(C)2001 Elsevier Science Inc. All rights reserved.
The short-term effect of metformin on fatty acid and glucose metabolism was studied in freshly incubated hepatocytes from 24-hr starved rats. Metformin (5 or 50 mM) had no effect on oleate or octanoate oxidation rates (CO2+ acid-soluble products), whatever the concentration used. Similarly, metformin had no effect on oleate esterification (triglycerides and phospholipid synthesis) regardless of whether the hepatocytes were isolated from starved (low esterification rates) or fed rats (high esterification rates). In contrast, metformin markedly reduced the rates of glucose production from lactate/pyruvate, alanine, dihydroxyacetone, and galactose. Using crossover plot experiments, it was shown that the main effect of metformin on hepatic gluconeogenesis was located upstream of the formation of dihydroxyacetone phosphate. Increasing the time of exposure to metformin (24 hr instead of 1 hr) led to significant changes in the expression of genes involved in glucose and fatty acid metabolism. Indeed, when hepatocytes were cultured in the presence of 50 to 500 muM metformin, the expression of genes encoding regulatory proteins: of fatty acid oxidation (carnitine palmitoyltransferase I), ketogenesis (mitochondrial hydroxymethylgltaryl-CoA synthase), and gluconeogenesis (glucose 6-phosphatase, phosphoenolpyruvate carboxykinase) was decreased by 30 to 60%, whereas expression of genes encoding regulatory proteins involved in glycolysis (glucokinase and liver-type pyruvate kinase) was increased by 250%. In conclusion, this work suggests that metformin could reduce hepatic glucose production through short-term (metabolic) and long-term (genic) effects. (C) 2001 Elsevier Science Inc. All rights reserved.