Cholesterols biosynthesis regulation

Steiner S, Gatlin CL, Lennon JJ, McGrath AM, Seonarain MD, Makusky AJ, Aponte AM, Esquer-Blasco R, Anderson NL. Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin. Toxicol Lett 2001 120 369-377. 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

Trifluoromethyl ketones and alcohol derivatives of squalene have been prepared in order to inhibit squalene epoxycyclase. This important enzyme regulates the biosynthesis of cholesterol. It bears a cysteine in its active site. Although these compounds have been shown to be good inhibitors, the involved mechanism is different from what was expected. Indeed, they do not inhibit squalene epoxycyclase, but they are substrates of this enzyme and are transformed into fluorohydroxysterols. The repression of the expression of HMG-CoA reductase is responsible for the observed inhibition of cholesterol biosynthesis. This repression comes from the back-regulation that is exerted by fluorohydroxysterols. Indeed, these compounds induce an important diminution of the cell activity of HMG-CoA reductase (Figure 7.66). °... 

Regulation of Cholesterol Biosynthesis Cholesterol in humans can be obtained from the diet or synthesized de novo. An adult human on a low-cholesterol diet typically synthesizes 600 mg of cholesterol per day in the liver. If the amount of cholesterol in the diet is large, de novo synthesis of cholesterol is drastically reduced. How is this regulation brought about ... 

The thiolase and HMG-CoA synthase exhibit some regulatory properties in rat liver (cholesterol feeding causes a decrease in these enzyme activities in the cytosol but not in the mitochondria). However, the primary regulation of cholesterol biosynthesis appears to be centered on the HMG-CoA reductase reaction. HMG-CoA reductase is found on the endoplasmic reticulum, has a molecular weight of 97,092, and consists of 887 amino acids in a single polypeptide chain. The sequence of the enzyme was deduced by Michael Brown and Joseph Goldstein from the sequence of a piece of complimentary DNA (cDNA) derived from mRNA that codes for the reductase. The enzyme... 

The rate of cholesterol biosynthesis appears to be regulated primarily by the activity of HMG-CoA reductase. This key enzyme is controlled by the rate of enzyme synthesis and degradation and by phosphorylation-dephosphorylation reactions. Synthesis of the mRNA for the reductase is inhibited by cholesterol delivered to cells by means of low-density lipoproteins (LDLs). 

The complexities of the regulation of cholesterol biosynthesis are explained in this chapter (13). 

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. 

All the major biosynthetic pathways use acetyl-CoA as the basic building block, and in each pathway the rate limiting enzyme is regulated by phosphorylation with the phosphorylated enzyme being active. In the biosynthesis of cholesterol, the rate limiting step is catalyzed by hydroxymethylglutaryl-CoA (HMG-CoA) reductase. Initially, three molecules of acetyl-CoA are condensed to produce /5-HMG-CoA. HMG-CoA reductase then uses two NADPH molecules to reduce HMG-CoA to mevalonate-CoA. The remaining steps in cholesterol biosynthesis are numerous and well-documented. 

A close connection exists between the regulation of cholesterol biosynthesis and uptake. When HMG-CoA reductase is inhibited, the cell responds by synthesizing more LDL receptors to ensure the uptake of cholesterol from the serum. When cholesterol is present in a high enough concentration in the cell, LDL receptors are not exported to the cell surface, an example of the phenomenon of down regulation. 

Figure 19.12 Regulation of liver acetyl-CoA carboxylase and cholesterol biosynthesis by phosphorylation. ACC indicates acetyl-CoA carboxylase. Bold arrow indicates activation of kinase kinase by fatty acyl-CoA. (Reproduced by permission from Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase a multi-substrate regulator of lipid metabolism. Trends Biochem Sci 14 20-23, 1989.)...

Staff writers. Regulation of cholesterol biosynthesis. Nutr Rev 45 92-94, 1987. 

HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis, and is subject to complex regulatory controls. A relatively constant level of cholesterol in the body (150-200 mg/dl) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Cholesterol from both diet and synthesis is utilised in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis. 

Figure 6.5 Regulation of HMG-CoA reductase. HMG-CoA reductase is active in the dephospho-rylated state phosphorylation (inhibition) is catalysed by reductase kinase, an enzyme whose activity is also regulated by phosphorylation by reductase kinase kinase. Hormones such as glucagon and adrenalin (epinephrine) negatively affect cholesterol biosynthesis by increasing the activity of the inhibitor of phosphoprotein phosphatase-1, PPI-1, (by raising cAMP levels) and so reducing the activation of HMG-CoA reductase. Conversely, insulin stimulates the removal of phosphates (and lowers cAMP levels), and thereby activates HMG-CoA reductase activity. Additional regulation of HMG-CoA reductase occurs through an inhibition of synthesis of the enzyme by elevation in intracellular cholesterol levels.

The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several Levels... 

---