Pallottini V, Marino M, Cavallini G, Bergamini E, Trentalance A
Department of Biology, University Roma Tre, Rome, Italy.
Biogerontology. 2003;4(6):371-8. doi: 10.1023/B:BGEN.0000006557.92558.60.
The physiological role of dolichol is not yet known but its accumulation in several tissues has been extensively reported in various physiological states or pathological conditions. Increased dolichol concentration in mammalian tissues during ageing has been also reported; in particular, we have previously indicated dolichol accumulation in liver as a new biomarker of ageing. However, the mechanism and the role of this accumulation is unknown. The aim of this work was to study the mechanism of the age-dependent dolichol accumulation analysing, in the liver and in the brain, the activity of the rate-limiting enzyme of isoprenoid biosynthesis, the 3-hydroxy 3-methylglutaryl CoA reductase, the dolichol and cholesterol synthesis on aged rats both fed ad libitum and caloric restricted. Furthermore, the dolichol and cholesterol levels in the plasma were assayed. The data shows that during ageing, the tissue dolichol accumulation is connected with the increase of 3-hydroxy 3-methylglutaryl CoA reductase activity and only in liver affected by diet restriction. In addition the aged rats maintain the capability to regulate their tissue cholesterol content by modifying cholesterol delivery into the blood. The amount of the 3-hydroxy 3-methylglutaryl CoA reductase enzyme detectable in liver and brain by Western blot analysis does not show significant changes during ageing. The presented data show that the accumulation of dolichol is related to the loss of enzymatic regulation characteristic of ageing. In fact, a higher mevalonate availability deriving from an increased expressed activity of HMGCoA-R could cause an increased production of dolichol.
多萜醇的生理作用尚不清楚，但在多种生理状态或病理状况下，其在多个组织中的蓄积已被广泛报道。衰老过程中哺乳动物组织中多萜醇浓度升高也有报道；特别是，我们之前已指出肝脏中多萜醇的蓄积是衰老的一种新生物标志物。然而，这种蓄积的机制和作用尚不清楚。这项工作的目的是通过分析自由进食和热量限制的老年大鼠肝脏和大脑中类异戊二烯生物合成限速酶3-羟基-3-甲基戊二酰辅酶A还原酶的活性、多萜醇和胆固醇的合成，来研究多萜醇随年龄蓄积的机制。此外，还检测了血浆中的多萜醇和胆固醇水平。数据表明，在衰老过程中，组织多萜醇的蓄积与3-羟基-3-甲基戊二酰辅酶A还原酶活性的增加有关，且仅在受饮食限制影响的肝脏中如此。此外，老年大鼠通过改变胆固醇向血液中的输送来维持调节其组织胆固醇含量的能力。通过蛋白质印迹分析在肝脏和大脑中检测到的3-羟基-3-甲基戊二酰辅酶A还原酶的量在衰老过程中未显示出显著变化。所呈现的数据表明，多萜醇的蓄积与衰老特有的酶调节丧失有关。事实上，HMGCoA-R表达活性增加导致甲羟戊酸可用性增加，可能会导致多萜醇产量增加。
