Cholesterol regulatory mechanisms

The two-step reduction of HMG-CoA to mevalonate (Fig. 22-1, step a)n 15 is highly controlled, a major factor in regulating cholesterol synthesis in the human liver.121617 The N-terminal portion of the 97-kDa 888-residue mammalian FlMG-CoA reductase is thought to be embedded in membranes of the ER, while the C-terminal portion is exposed in the cytoplasm.16 Tire enzyme is sensitive to feedback inhibition by cholesterol (see Section D, 2). The regulatory mechanisms include a phosphorylation-dephosphorylation cycle and control of both the rates of synthesis and of proteolytic degradation of this key en-... 

The second regulatory mechanism involves the degra-dation of HMG-CoA reductase. As stated in chapter 29 the amount of an enzyme in a cell is determined by both its rate of synthesis and its rate of degradation. The rate of degradation of the reductase appears to be modulated by the supply of cholesterol. Thus, when cholesterol is abundant, the rate of enzyme degradation is twice as fast as when there is a limited supply of cholesterol. The effect of cholesterol on enzyme degradation is mediated by the membrane domain of the enzyme. 

Goldstein, I. L., and M. S. Brown, Regulation of the mevalon-ate pathway. Nature 343 425-430, 1990. This article describes regulatory mechanisms for cholesterol biosynthesis within the context of the regulation of the biosynthesis of other isoprenoid derivatives. 

Members of a family of nuclear transcription factors called sterol regulatory element-binding proteins (SREBP) are responsible for the regulation of these cholesterol feedback mechanisms. SREBP are able to activate a number of genes encoding for proteins involved in the homeostasis of cholesterol and other lipids, including the LDL receptor gene itself. 

As we will see shortly, all four regulatory mechanisms are modulated by receptors that sense the presence of cholesterol in the blood. 

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 is also subject to translational control by a mevalonate-derived non-sterol regulator (D. Peffley, 1985 M. Nakanishi, 1988). Tliis component of the regulatory mechanism can be observed only when cultured cells are acutely incubated with statins, which block mevalonate formation. Under those conditions, sterols have no effect on HMG-CoA reductase mRNA translation however, mevalonate reduces the HMG-CoA mRNA translation by 80% with no change in mRNA levels. Translational control of hepatic HMG-CoA reductase by dietary cholesterol was shown in an animal model in which polysome-associated HMG-CoA reductase mRNA was analyzed in cholesterol-fed rats (C.M. Chambers, 1997). It was found that cholesterol feeding increased the portion of mRNA associated with translationally inactive monosomes and decreased the portion of mRNA associated with translationally active polysomes. The mechanism of HMG-CoA reductase translational control has not been elucidated. 

As early as 1966, Siperstein et al. showed negative feed-back control of cholesterol biosynthesis to be defective in transplantable hepatomas. More recently Bricker Levey (1972) demonstrated unsupressible cholesterol and fatty acid synthesis by cyclic nucleotides in hepatomas and indicated a deletion of this regulatory mechanism of lipogenesis. 

The full extent to which saponins reduce cholesterol absorption requires further study. Because of the large number of saponins present in the food supply, it is possible that all of the mechanisms discussed earlier contribute to reduced cholesterol absorption. Unlike plant sterols in which their mode of action is relatively well defined, there are probably multiple effects of saponins within the intestinal tract, including their ability to interact with other dietary constituents and the ability of some saponins to be absorbed systemically. The regulatory effects of saponins on cellular cholesterol transport have not been examined. 

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