Non-steroidal isoprenoids

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. 

Cholesterol synthesis is essential for normal development and maintenance of tissues that cannot obtain cholesterol from plasma lipoproteins, such as brain [3]. Furthermore, the biosynthetic pathway supplies non-steroidal isoprenoids that are required by all cells. Thus, it is not surprising that metabolic defects in the cholesterol biosynthetic pathway have devastating physiological consequences [8,9]. 

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