Regulating cholesterol synthesis

Several other mechanisms also regulate cholesterol synthesis (Fig. 21-44). Hormonal control is mediated... 

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-... 

Qureshi (168) first isolated tocotrienols from barley and proved that they could suppress the hepatic production of cholesterol through their ability to suppress the activity of the enzyme HMG-CoA reductase, which regulates cholesterol synthesis in the liver. 

Fig. 1. Overview of the metabolic and transport pathways that control cholesterol levels in mammalian cells. Cholesterol is synthesized from acetyl-CoA and the four key enzymes that regulate cholesterol synthesis are indicated. Cells also obtain cholesterol by uptake and hydrolysis of LDL s cholesteryi esters (CE). End products derived from cholesterol or intermediates in the pathway include bile acids, oxysterols, cholesteryi esters, and non-steroidal isoprenoids. ACAT, acyl-CoA cholesterol acyltransferase.

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

Another explanation to palm oil hypocholesterolemic action would be the presence of tocotrienols. They are admittedly considered hypocholesterolemic once they regulate cholesterol synthesis through 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inactivation - enzyme that primarily synthesizes the cholesterol [147]. 

The data discussed here so far provides a basis for proposing a mechanism (1 ) that may regulate the amount of unesterified cholesterol present in the cell (Fig. 8). In the liver cell, the utilization of cholesterol is regulated by ACAT and cholesterol 7a-hydroxylase. Both of these enzymes appear to be active in the phosphorylated state. The enzyme which regulates cholesterol synthesis, that is, HMG-CoA reductase, is active when dephosphorylated. Therefore, synthesis and utilization are oppositely regulated by phosphorylation/dephosphorylation. 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Figure 26-4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Asterisk See Figure 18-6.

The lipid compositions of plasma membranes, endoplasmic reticulum and Golgi membranes are distinct 26 Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues 26 In adult brain most cholesterol synthesis occurs in astrocytes 26 The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling 27 The structure and roles of membrane microdomains (rafts) in cell membranes are under intensive study but many aspects are still unresolved 28... 

A summary of some of these processes is as follows synthesis of phospholipids and cholesterol de novo synthesis of ribonucleotides synthesis of RNA de novo synthesis of deoxyribonucleotides regulation of synthesis of deoxyribonucleotides salvage pathways duplication of DNA transcription and translation (polypeptide synthesis). After this series of topics, those of fuels and ATP generation, mitosis and, finally, regulation of the cycle, are described and discussed. 

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.

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... 

Squalene takes part in metabolism as precursor for synthesis of steroids and structurally quite similar to (3-carotene, coenzyme qlO, vitamins Ki, E, and D. The squalene in skin and fat tissue comes from endogenous cholesterol synthesis as well as dietary resources in people who consume high amounts of olive and fish oil especially shark liver (Gershbein and Singh, 1969). Squalene is synthesized by squalene synthase which converts two units of farnesyl pyrophosphate, direct precursor for terpenes and steroids, into squalene. As a secosteroid, vitamin D biosynthesis is also regulated by squalene. Moreover, being precursor for each steroid family makes squalene a crucial component of the body. 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Twelve reviews cover the structure, synthesis, and metabolism of lipoproteins, regulation of cholesterol synthesis, and the enzymes LCAT and lipoprotein lipase. 

---