Regulation of receptor-mediated sterol uptake

The regulatory events which result from the receptor-mediated uptake and degradation of LDL in cultured human fibroblasts are shown in Fig. 4. These events can be described in the context of cyclic changes that occur in cultured human fibroblasts in response to the absence or presence of LDL (see Fig. 5). When LDL is 

Exposure of cholesterol-starved cells to LDL is followed by massive buildup of intracellular free cholesterol pools. HMG-CoA reductase is suppressed, shutting down cellular cholesterol synthesis [84,85]. ACAT is stimulated as much as 500-fold by a process that apparently is independent of protein synthesis [86]. Subsequently, the number of LDL receptors declines dramatically with a calculated half-life of 15-20 h [29,31]. Since the rate of decline under conditions which block protein synthesis is comparable to the LDL-mediated rate of decline [29,87], down-regulation may be due to suppression of receptor synthesis. Excess eholesterol is esterified and stored in the c)rtoplasm as cholesteryl esters. A steady-state characterized by large cholesteryl ester and free cholesterol pools and by basal levels of both HMG-CoA reductase and LDL receptors is ultimately attained. This regulatory mechanism allows cells to control their rate of cholesterol uptake, synthesis, and storage in response to the available supply of lipoprotein cholesterol. 

HMG-CoA reductase activity and LDL receptor levels always appear to change in the same direction in cells exposed to different levels of LDL. Similarly, a mutant line of Chinese hamster ovary (CHO) cells exposed to delipidated serum expresses low levels of both HMG-CoA reductase and LDL receptor activities compared to normal cells [88], Taken together, this evidence suggests coordinate expression of these two activities. 

While the LDL pathway for control of cholesterol uptake was elucidated using cultured cells, it also appears to be functional in vivo. The pattern of regulation depicted in Fig. 5 has been confirmed in freshly isolated blood leukocytes and lymphocytes [89-92]. In addition, administration of 4-aminopyrazolepyrimidine, a drug which suppresses lipoprotein release from animal liver [93], elevates HMG-CoA reductase levels and cholesterol synthesis in non-hepatic tissues [94,95]. These observations are consistent with the hypothesis that non-hepatic cells exhibit a low rate of cholesterol synthesis because they utilize cholesterol synthesized by the liver and present in the plasma lipoproteins [96], 

Regulation associated with the receptor-mediated uptake of lipoproteins by the apo-E receptor of liver is somewhat limited. While there is a marked suppression of HMG-CoA reductase activity and cholesterol synthesis [97], liver apo-E receptors are not drastically down-regulated [12] as are LDL receptors in non-hepatic tissues. 

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