Regulating sterol synthesis

More direct evidence that cholesterol itself regulates sterol synthesis in the intestine has been obtained in studies using various in vitro techniques such as organ culture of intestinal mucosa. In such a system, cholesterol dissolved in ethanol... 

A20. Andersen, J. M., and Dietschy, J. M., Regulation of sterol synthesis in adrenal gland of the rat by both high and low density human plasma lipoproteins. Biochem. Biophys. Res. Common. 72, 880-885 (1976). 

SREBPs are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus up-regulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative-feedback loop. 

Patients with familial hypercholesterolaemia exhibit lower levels of plasma cholesterol after an operation for portacaval anastomosis, and it has now been shown in rats that such an operation causes an increase in HMG-CoA reductase and cholesterol 7a -hydroxylase activities. Many transplantable human and rodent hepatomas do not control the rate of sterol biosynthesis and HMG-CoA reductase levels in response to dietary cholesterol as normal liver cells do. However, certain hepatoma cells have now been found that, although lacking feedback regulation of choles-terologenesis in vivo, retain their regulatory ability in vitro It thus appears that malignant transformation is not necessarily linked to the loss of regulation by the cell of HMG-CoA reductase activity or sterol synthesis. 

HMG-CoA reductase is the rate-determining enzyme of sterol synthesis, and its activity is regulated by competitive inhibition by compounds that bind to the same site as HMG-CoA. It is also regulated by substances that bind to other (allosteric) sites on the enzyme molecule. Inhibitors of this enzyme (e.g., simvastatin) are used as medicines to reduce cholesterol in patients whose cholesterol levels are too high. Through feedback inhibition, cholesterol is a strong inhibitor of the enzyme itself. No fungicides with this mode of action have yet been developed, but the possibility that they will be exists. 

The enzymes so far described are identical, with respect to the reactions catalyzed, to the enzymes that make ketone bodies. Since these pathways are physically separated within the cell, it would seem that regulation of sterol synthesis could reside in this region of the pathway. However, the key regulatory step in cholesterol biosynthesis is HMG-CoA reductase (Chapter 2). A book on this protein has been published recently [29], and among others Qureshi and Porter have also reviewed this enzyme [12]. Comments on this protein will be restricted to noting a few salient features that will enable the reader to progress without referring to other sources. 

L. J. Goad, How is Sterol synthesis regulated in higher plants Blochem. Soc. Trans. 11 548 (1983)... 

Figure 8-6. Hormonal regulation of cholesterol synthesis by reversible phosphorylation of HMG CoA reductase. Availability of mevalonic acid as the fundamental building block of the sterol ring system controls flux through the pathway that follows. cAMP, cyclic adenosine monophosphate HMG CoA, hydroxymethylglutary I CoA.

Lipids have several important functions in animal cells, which include serving as structural components of membranes and as a stored source of metabolic fuel (Griner et al., 1993). Eukaryotic cell membranes are composed of a complex array of proteins, phospholipids, sphingolipids, and cholesterol. The relative proportions and fatty acid composition of these components dictate the physical properties of membranes, such as fluidity, surface potential, microdomain structure, and permeability. This in turn regulates the localization and activity of membrane-associated proteins. Assembly of membranes necessitates the coordinate synthesis and catabolism of phospholipids, sterols, and sphingolipids to create the unique properties of a given cellular membrane. This must be an extremely complex process that requires coordination of multiple biosynthetic and degradative enzymes and lipid transport activities. 

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