Sterol acyltransferase

Phosphatidylcholine-sterol acyltransferase— lecithin-cholesterol acyltransferase (LCAT) ... 

Sterol acyltransferase (SGTase) and steryl ester hydrolase (SEHase)... 

Phosphatidylcholine-sterol acyltransferase deficiency see Inborn errors of metabolism. 

D-bifunctional protein deficiency [5], 2-methyl acyl-CoA racemase (AMACR) deficiency [3] and sterol carrier protein (SCP-x) deficiency [6], the disorders of etherphospholipid biosynthesis (dihydroxyacetone phosphate acyltransferase and alkyl- dihydroxyacetone phosphate synthase deficiency) [2], the disorders of phytanic acid alpha-oxidation (Refsum disease) [15], and the disorders of glyoxylate detoxification with hyperoxaluria type 1 as caused by alanine glyoxylate aminotransferase deficiency as a sole representative. 

Fig. 4. Potential sources of the immediate precursor pool of unesterified cholesterol available for mitochondrial steroidogenesis. ACAT, microsomal acyl coenzyme A cholesterol acyltransferase SEH, sterol ester hydrolase. From Ref. 14.

Unesterified sterols modulate the function of eukaryotic membranes. In human cells, sterol is esterified to a storage form by acyl-co-enz)me A (CoA) cholesterol acyltransferase (SGTase). In plants, free sterols are associated mainly with microsomal membranes, whereas the steryl esters are stored in lipid granules. The esterification process may, thus, allow regulation of the... 

Important elements of sterol metabolism can also be used to elucidate where in the cell a particular precursor has moved [7]. The arrival of cholesteryl esters within lysosomes is revealed by cleavage of the fatty acid to yield free cholesterol. The subsequent transport of cholesterol to the ER can be monitored by the action of acyl-CoA cholesterol acyltrans-ferase (Chapter 14) that results in the formation of new molecular species of cholesteryl esters. In addition, sphingomyelinase treatment of the cell surface induces cholesterol movement from the plasma membrane to the ER where its arrival can likewise be monitored by the action of acyl-CoA cholesterol acyltransferase. Import of cholesterol into mitochondria (usually restricted to steroidogenic cells) can be followed by side-chain cleavage reactions that produce pregnenolone [8]. Movement of pregnenolone out of mitochondria can be followed by oxidations at positions 3, 17, and 21, which occur in the ER. 

The LDL receptor is a key component in the feedback-regulated maintenance of cholesterol homeostasis [1]. In fact, as an active interface between extracellular and intracellular cholesterol pools, it is itself subject to regulation at the cellular level (Fig. 2). LDL-derived cholesterol (generated by hydrolysis of LDL-bome cholesteryl esters) and its intracellularly generated oxidized derivatives mediate a complex series of feedback control mechanisms that protect the cell from over-accumulation of cholesterol. First, (oxy)sterols suppress the activities of key enzymes that determine the rate of cellular cholesterol biosynthesis. Second, the cholesterol activates the cytoplasmic enzyme acyl-CoA cholesterol acyltransferase, which allows the cells to store excess cholesterol in re-esterified form. Third, the synthesis of new LDL receptors is suppressed, preventing further cellular entry of LDL and thus cholesterol overloading. The coordinated regulation of LDL receptors and cholesterol synthetic enzymes relies on the sterol-modulated proteolysis of a membrane-bound transcription factor, SREBP, as described in Chapter 14. 

Cholesteryl ester synthase and fatty acid synthase, but also sterol 6>-acyltransferase, perform conjugations of various... 

Scheme 113.1 Schematic overview of cholesterol metabolism and main proposed mechanisms of action of phytosterols. 1. The absorption of dietary and/or biliary cholesterol is reduced by competition with PS for incorporation into mixed micelles. 2. Esterification of free cholesterol in the enterocyte is reduced by competition with PS for ACAT-2 enzyme. 3. Upregulation of the heterodimer ABCG5/G8 by PS can increase intestinal and hepato-biliar secretion. 4. Upregulation of ABCAl by PS can increase the incorporation of sterols into nascent HDL. 5. Increased cholesterol excretion via TICE. 6. Although it is not directly mediated by PS, the lower levels of hepatic cholesterol can lead to a lower VLDL secretion and upregulation of LDL receptor, which improves the clearance of plasma cholesterol. Abbreviations FC free cholesterol, CE cholesterol esters, ACAT-2 Acyl-CoA cholesterol O-acyltransferase 2, CM chylomicron, CMR chylomicron remnant, TICE transintestinal cholesterol efflux, LDL low-density lipoprotein, IDL intermediate-density lipoprotein, HDL high-density lipoprotein...

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