Cholesterol biosynthesis, control

A series of hypocholesteremic agents were isolated from Monascus and named monacolin J, K, and L. These polyketides were first isolated from cultures of Penicillium citrinum and they can inhibit specifically the enzyme controlling the rate of cholesterol biosynthesis. They are currently used in China in traditional and modem medicine. 

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. 

Inhibition of cholesterol biosynthesis (% of control) (human hepatocyte cells) io- M 10- M... 

Intermediate sterol levels higher than observed (if observed at all) in control samples in conjunction with specific clinical symptoms may point to a defect in cholesterol biosynthesis and should be followed up by additional studies as outlined under section 5.1.8. Although cholesterol levels are often reduced, they maybe (low) normal. 

Fig. 5.1.3 Sterol analysis in patients with defective cholesterol biosynthesis. Gas chromatography-mass spectrometry analysis of trimethylsilyl derivatives of sterols extracted from primary skin fibroblasts of a control subject, a Smith-Lemli-Opitz syndrome (SLOS) patient, and a Con-radi-Hunermann syndrome (CDPX2) patient, and lymphoblasts of a desmosterolosis patient cultured in lipoprotein-deficient medium reveals the accumulation of sterol intermediates indicative of a defect in cholesterol biosynthesis. Similar spectra can be obtained by sterol analysis of the plasma of such patients...

In addition to its role as an intermediate in cholesterol biosynthesis, isopentenyl pyrophosphate is the activated precursor of a huge array of biomolecules with diverse biological roles (Fig. 21-48). They include vitamins A, E, and K plant pigments such as carotene and the phytol chain of chlorophyll natural rubber many essential oils (such as the fragrant principles of lemon oil, eucalyptus, and musk) insect juvenile hormone, which controls metamorphosis dolichols, which serve as lipid-soluble carriers in complex polysaccharide synthesis and ubiquinone and plastoquinone, electron carriers in mitochondria and chloroplasts. Collectively, these molecules are called isoprenoids. More than... 

HMG CoA reductase, the rate-limiting enzyme, is the major control point for cholesterol biosynthesis, and is subject to different kinds of metabolic control. 

The sequence of cholesterol biosynthesis begins with a condensation in the cytosol of two molecules of acetyl-CoA in a reaction catalyzed by thiolase (fig. 20.3). The next step requires the enzyme /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) synthase. This enzyme catalyzes the condensation of a third acetyl-CoA with /3-ketobutyryl-CoA to yield HMG-CoA. HMG-CoA is then reduced to mevalonate by HMG-CoA reductase. The activity of this reductase is primarily responsible for control of the rate of cholesterol biosynthesis. 

Cholesterol biosynthesis is also controlled by the plasma levels of low-density lipoproteins, which we discuss in the context of lipoprotein metabolism later in this chapter. 

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). 

In vitro, allicin and related compounds inhibit HMG-CoA reductase, which is involved in cholesterol biosynthesis (see Chapter 35 Agents Used in Hyperlipidemia). Several clinical trials have investigated the lipid-lowering potential of garlic. Some have shown significant reductions in cholesterol and others no effect. The most recent meta-analysis suggested a minor (5%) reduction of total cholesterol that was insignificant when dietary controls were in place. 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Cholesterol can be obtained either from the diet or it can be synthesized de novo, mainly in the liver. Cholesterol is transported round the body in lipoprotein particles (see Topic K6). The rate of synthesis of cholesterol is dependent on the cellular level of cholesterol. High levels of cholesterol and its metabolites control cholesterol biosynthesis by ... 

The other system controlling cholesterol biosynthesis involves both the cytosolic HMG-CoA synthase and the ER enzyme HMG-CoA reductase and is based on the cellular levels of respective mRNAs. Increasing free cholesterol decreases both enzyme activities by decreasing the levels of their mRNAs and increasing enzyme degradation processes. The half-life of HMG-CoA reductase may be as short as 1.7 h. Cellular uptake of LDL maintains cholesterol biosynthesis at a relatively low level, and this is achieved through an LDL degradation product-free cholesterol. Some authorities have maintained that hydroxylated... 

Several factors control cholesterol biosynthesis either directly or indirectly. Which is not a factor ... 

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. 

HMG-CoA reductase activity is the primary means for controlling the level of cholesterol biosynthesis. 

The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step, 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis, as will be discussed shortly. 

The major site of steroid synthesis in animals has been considered to be the liver, but recently (1975) this has been disputed and detailed studies now show that sterol synthesis in guinea pig occurs more readily in ileum and lung than in liver under a variety of conditions" " and a brief study indicates similar sites of biosynthesis in swine." All tissues of guinea pig studied had an active feedback system controlling cholesterol biosynthesis and the results of feeding cholesterol and cholestyramine" showed that both the former and possibly bile acids suppress cholesterol synthesis in the liver to a far lesser extent than in the small intestine. 

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