HMG-CoA reductase, in cholesterol

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Statins Inhibit cholesterol synthesis in the liver and decrease LDL by inhibiting HMG CoA reductase in cholesterol biosynthesis, resulting in reduction of LDL after 2 weeks. 

Know about the role of HMG-CoA reductase in cholesterol synthesis. 

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

Recently, we [67] have described the reduction of the methyl ester of 4-chloro-3-oxobutanoic acid (39) to the methyl ester of S-( )-4-chloro-3-hydroxy-butanoic acid (40) (Fig. 13) by cell suspensions of Geotrichum candidum SC 5469., S ( )-(40) is a key chiral intermediate in the total chemical synthesis of a cholesterol antagonist (SQ 33600), which acts by inhibiting hydroxymethylglu-taryl CoA (HMG CoA) reductase. In the biotransformation process, a reaction... 

Liu L and Yeh YY (2002) S-alk(en)yl cysteines of garlic inhibit cholesterol synthesis by deactivating HMG-CoA reductase in cultured rat hepatocytes. Journal of Nutrition 132, 1129-34. 

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. 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

The higher activity of HMG-CoA reductase in obese patients in combination with a high calorie diet increases the synthesis of cholesterol. 

When rat hepatocytes are treated with insulin, glucagon or cAMP, the proportion of HMG-CoA reductase in the active, dephosphorylated form, but not HMG-CoA reductase protein levels, rapidly shifts. Insulin increases, and cAMP or glucagon decreases, the fraction of HMG-CoA reductase in an active, dephosphorylated form. These shifts are paralleled by changes in the rate of cholesterol synthesis [152]. 

The drug dichloroacetate, which lowers serum cholesterol levels in rats, decreases the proportion of hepatic HMG-CoA reductase in the active, dephosphorylated form within an hour after administration [160],... 

Similar problems have compUcated the quantitation of HMG-CoA reductase activity as a measure of the rate of cholesterol synthesis. For example, it has not been established as firmly for the intestine as for the hver that this enzyme is rate limiting to the overall synthesis of the cholesterol molecule [23]. Furthermore, HMG-CoA reductase in both the intestine and liver is subject to a phosphorylation-dephosphorylation reaction that modifies enzyme activity and is involved in the activation of an inactive (phosphorylated) to an active (dephos-phorylated) form during homogenization of the mucosa [24,25]. Finally, HMG-CoA reductase is incompletely recovered from the mucosa during preparation of micro-somes [26,27] and is very sensitive to inactivation by proteases present in the intestine [28]. These various technical problems have led to considerable confusion with respect to various aspects of intestinal cholesterol synthesis and have made it difficult to interpret quantitatively some of the results presented below. 

A coupling appears to exist between the rate-limiting enzyme in the biosynthesis of cholesterol, HMG-CoA reductase, and cholesterol 7a-hydroxylase. The two enzymes seem to be located close to each other on the endoplasmic reticulum membrane [66], and the two activities covariate under most conditions. Results from both in vivo and in vitro experiments show that newly synthesized cholesterol is the preferred substrate for cholesterol 7a-hydroxylase. In an early study by Staple and Gurin, it was shown that the bile acids in bile had a higher radioactivity than cholesterol after administration of labelled acetate to rats [67]. Bjorkhem and Danielsson found that the specific radioactivity of 7a-hydroxycholesterol was higher than that of cholesterol after incubation of labelled mevalonate with the 10000 x g supernatant fluid of a rat liver homogenate [50]. Balasubramaniam et al. showed that 7a-hydroxycholesterol isolated from the livers of rats after intravenous administration of labelled cholesterol had a lower specific radioactivity than cholesterol [58]. Cronholm and collaborators measured the incorporation of isotope from [1- H2]-,... 

An elegant demonstration of the relation between the activity of HMG-CoA reductase and cholesterol 7a-hydroxylase was performed by Mitropoulos et al. It was shown that administration of mevalonic acid to rats resulted in an increase of the size of the intracellular pool of cholesterol that is in the environment of the rate-limiting enzyme in cholesterol biosynthesis [71]. Since this enzyme seems to be located close to the cholesterol 7a-hydroxylase [66,72], and the activity of the latter enzyme was stimulated, it was suggested that the increased amount of free cholesterol available was the actual stimulating factor for cholesterol 7a-hydroxylase. 

The regulation of the overall biosynthesis of bile acids has been studied intensively during the last decade, and only a small fraction of all the pubhcations can be reviewed here. Cholesterol 7a-hydroxylase is the rate-limiting enzyme in the biosynthesis of both chohc acid and chenodeoxycholic acid. The publications in which a correlation has been demonstrated between bile acid biosynthesis and 7a-hydroxyl-ation of cholesterol have been reviewed by Myant and Mitropoulos [59]. In the present review, emphasis will be put on the feedback regulation of the cholesterol 7a-hydroxylase by the bile-acid flux through the hver, the relation between HMG-CoA reductase and cholesterol 7 -hydroxylase and possible mechanisms for the regulation. 

The most important information concerning mechanisms of regulation of cholesterol 7a-hydroxylase is summarized in the model shown in Fig. 14. In view of the importance of HMG-CoA reductase for cholesterol 7a-hydroxylase activity, some important modulators of HMG-CoA reductase activity have also been included (cf. Chapter 2). It should be pointed out that the regulation of biosynthesis of cholesterol shown in Fig. 14 is oversimplified. For a discussion of the regulation of HMG-CoA reductase, the reader is referred to Chapter 2 and a recent review by Brown and Goldstein [246]. 

Lovastatin (Mevacor) Pravastatin (Pravachol) Simvastatin (Zocor) Inhibits HMG CoA reductase in liver. This enzyme catalyzes the rate-limiting step in cholesterol synthesis. u u i Cholesterol, LDL, VLDL, triglyc. T HDL ... 

Fig. 12-11 Cholesterol synthesis and the regulation of HMG-CoA reductase. (A) Overview of the pathway showing negative feedback control of HMG-CoA reductase by cholesterol. Dashed straight arrows denote more than one enzymic reaction. (B) Synthesis of HMG-CoA, in two steps. (C) Details of the conversion of HMG-CoA into isopen-tenyl pyrophosphate, the building block for cholesterol and terpenes (Sec. 12.1).

Lycopene is also known to decrease the expression of HMG-CoA reductase in macrophage cell cultures, based on the results of a small clinical study where 60mg lycopene daily was found to decrease seram LDL cholesterol. Suppression of HMG-CoA reductase activity acts to retard cancer induction and slow cellular growth. " A main reason for this is that synthesis of the isoprenoid dolichol during G1 phase is crucial for cell surface expression of insulin-like growth factor I (IGF-I) receptors, and cells that caimot synthesize dolichol experience an effective deficiency of IGF-I activity. ... 

Decreased HMG-CoA reductase and cholesterol concentrations in the hypomyelinated frontal brain region in the PKU mouse... 

The major pathway for the formation of MVA in yeast and mammalian systems is shown in Fig. 2. Acetyl-CoA and acetoacetyl-CoA are condensed by the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) synthase (HMG-CoA acetoacetyl-CoA lyase, E.C. 4.1.3.5) to form 3-hydroxy-3-methylglu-taryl-CoA (HMG-CoA). In a two-step reduction, HMG-CoA is then reduced to MVA in a reaction catalyzed by the enzyme HMG-CoA reductase. In the first step of this reaction, the CoA hemithioacetal of mevaldic acid is formed. In the second step, this compound is reduced to MVA both steps require NADPH. Hydroxymethylglutaryl-CoA reductase is an important control point in the regulation of cholesterol biosynthesis in mammalian systems. The HMG-CoA reductase enzymes from yeast and mammalian liver have been purified to homogeneity, and some of their properties have been determined. This work is covered in detail in several reviews (Beytia and Porter, 1976 Rodwell et al., 1976 Kandutsch et al., 1978). 

---