Stimulation of hepatic cholesterol biosynthesis by fatty acids. Effects of oleate on cytoplasmic acetoacetyl-CoA thiolase, acetoacetyl-CoA synthetase and hydroxymethylglutaryl-CoA synthase.
Stimulation of hepatic cholesterol biosynthesis by fatty acids. Effects of oleate on cytoplasmic acetoacetyl-CoA thiolase, acetoacetyl-CoA synthetase and hydroxymethylglutaryl-CoA synthase.
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脂肪酸刺激肝脏胆固醇生物合成。
DOI：
10.1042/bj2580563
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Heimberg,M
中科院分区：
文献类型：
--
作者：
Salam,WH;Wilcox,HG;Cagen,LM;Heimberg,M
在离体灌流的大鼠肝脏中，研究了油酸对细胞溶质HMG-CoA（3-羟基-3-甲基戊二酰-CoA）合酶、AcAc-CoA（乙酰乙酰-CoA）硫解酶和AcAc-CoA合成酶以及微粒体HMG-CoA还原酶活性的影响。结合牛血清白蛋白的油酸或单独的白蛋白以足以在灌注期间维持0.61 +/- 0.05 mM脂肪酸的平均浓度的速率输注4 h。在灌注结束时分离肝细胞质和微粒体组分。油酸同时增加了正常喂养大鼠和禁食24小时动物肝脏中细胞溶质胆固醇生物合成酶的活性1.4-2.7倍。这些影响伴随着增加净分泌的肝脏胆固醇和三酰甘油的极低密度脂蛋白（VLDL）。我们证实了本实验室先前报道的油酸刺激微粒体HMG-CoA还原酶的观察结果。在灌注肝脏的细胞质中，AcAc-CoA硫解酶活性的增加的特征在于Vmax的增加。酶对AcAc-CoA的表观Km没有任何变化。相反，油酸降低HMG-CoA合酶对Ac-CoA的Km，而不改变Vmax。的酶。Vmax。AcAc-CoA合成酶的Km值随着油酸的增加而增加，并且乙酰乙酸的Km值有小幅增加的趋势。这些数据使我们能够得出结论，提供肝胆固醇生成所需的HMG-CoA的酶受到刺激，HMG-CoA还原酶也受到生理底物脂肪酸的刺激，脂肪酸增加了肝胆固醇合成和胆固醇分泌的速率。此外，我们认为，这些脂肪酸对肝脏胆固醇代谢的影响是由于刺激的VLDL中的三酰甘油的分泌脂肪酸，和胆固醇的绝对需求作为一个重要的结构表面组成部分的VLDL必需的三酰甘油从肝脏的运输。
The effects of oleic acid on the activities of cytosolic HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) synthase, AcAc-CoA (acetoacetyl-CoA) thiolase and AcAc-CoA synthetase, as well as microsomal HMG-CoA reductase, all enzymes in the pathway of cholesterol biosynthesis, were studied in the isolated perfused rat liver. Oleic acid bound to bovine serum albumin, or albumin alone, was infused for 4 h at a rate sufficient to sustain an average concentration of 0.61 +/- 0.05 mM fatty acid during the perfusion. Hepatic cytosol and microsomal fractions were isolated at the termination of the perfusion. Oleic acid simultaneously increased the activities of the cytosolic cholesterol-biosynthetic enzymes 1.4-2.7-fold in livers from normal fed rats and from animals fasted for 24 h. These effects were accompanied by increased net secretion by the liver of cholesterol and triacylglycerol in the very-low-density lipoprotein (VLDL). We confirmed the observations reported previously from this laboratory of the stimulation by oleic acid of microsomal HMG-CoA reductase. In cytosols from perfused livers, the increase in AcAc-CoA thiolase activity was characterized by an increase in Vmax. without any change in the apparent Km of the enzyme for AcAc-CoA. In contrast, oleic acid decreased the Km of HMG-CoA synthase for Ac-CoA, without alteration of the Vmax. of the enzyme. The Vmax. of AcAc-CoA synthetase was increased by oleic acid, and there was a trend towards a small increase in the Km of the enzyme for acetoacetate. These data allow us to conclude that the enzymes that supply the HMG-CoA required for hepatic cholesterogenesis are stimulated, as is HMG-CoA reductase, by a physiological substrate, fatty acid, that increases rates of hepatic cholesterol synthesis and cholesterol secretion. Furthermore, we suggest that these effects of fatty acid on hepatic cholesterol metabolism result from stimulation of secretion of triacylglycerol in the VLDL by fatty acids, and the absolute requirement of cholesterol as an important structural surface component of the VLDL necessary for transport of triacylglycerol from the liver.