The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1
The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1
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DOI：
10.1074/jbc.m005488200
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发表时间：
2000-09-29
影响因子：
4.8
通讯作者：
Ntambi, JM
中科院分区：
文献类型：
--
作者：
Miyazaki, M;Kim, YC;Ntambi, JM
硬脂酰辅酶A去饱和酶（SCD）是生物合成油酸酯和棕榈油酸酯所需的微粒体酶，油酸酯和棕榈油酸酯是膜磷脂、甘油三酯和胆固醇酯的主要单不饱和脂肪酸。SCD的两种充分表征的同种型，SCD 1和SCD 2，存在于小鼠中。大多数小鼠组织表达SCD 1和2，但肝脏除外，其主要表达SCD 1同种型。我们发现，asebia小鼠的SCD 1（SCD-/-）基因的天然突变纯合子缺乏肝胆固醇酯和甘油三酯，尽管存在正常的活动的酰基辅酶A：胆固醇酰基转移酶和甘油磷酸酰基转移酶，负责胆固醇酯和甘油三酯合成的酶，分别在这些小鼠的肝脏。给SCD-/-小鼠喂食补充有三油酸甘油酯或三棕榈油酸甘油酯的饮食导致肝脏中16：1和18：1水平的增加，但未能将胆固醇酯和甘油三酯的18：1和16：1水平恢复到正常小鼠中发现的水平。与正常动物相比，SCD-/-小鼠在VLDL和LDL脂蛋白级分中具有非常低的甘油三酯水平。将SCD 1表达载体瞬时转染到中国仓鼠卵巢细胞中导致SCD活性增加和胆固醇酯化为胆固醇酯。综上所述，我们的观察结果表明，由SCD 1产生的油酰辅酶A和棕榈油酰辅酶A是在肝脏中合成足够的胆固醇酯和甘油三酯所必需的，并表明SCD 1活性的调节在细胞胆固醇稳态机制中起着重要作用。
Stearoyl-CoA desaturase (SCD) is a microsomal enzyme required for the biosynthesis of oleate and palmitoleate, which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides, and cholesterol esters. Two well characterized isoforms of SCD, SCD1 and SCD2, exist in the mouse. Most mouse tissues express SCD1 and 2 with the exception of the liver, which expresses mainly the SCD1 isoform. We found that asebia mice homozygous for a natural mutation of the gene for SCD1 (SCD-/-) are deficient in hepatic cholesterol esters and triglycerides despite the presence of normal activities of acyl-CoA:cholesterol acyltransferase and glycerol phosphate acyltransferase, the enzymes responsible for cholesterol ester and triglyceride synthesis, respectively, in the liver of these mice. Feeding diets supplemented with triolein or tripalmitolein to the SCD-/- mice resulted in an increase in the levels of 16:1 and 18:1 in the liver but failed to restore the 18:1 and 16:1 levels of the cholesterol ester and triglycerides to the levels found in normal mice, The SCD-/- mouse had very low levels of triglycerides in the VLDL and LDL lipoprotein fractions compared with the normal animal. Transient transfection of an SCD1 expression vector into Chinese hamster ovary cells resulted in increased SCD activity and esterification of cholesterol to cholesterol esters. Taken together, our observations demonstrate that the oleoyl-CoA and palmitoleyl-CoA produced by SCD1 are necessary to synthesize enough cholesterol esters and triglycerides in the liver and suggest that regulation of SCD1 activity plays an important role in mechanisms of cellular cholesterol homeostasis.