Disorders of Cholesterol Biosynthesis

Arch Dis Child 1998;78:185–189 185 CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.78.2.185 on 1 February 1998. Downloaded from Disorders of cholesterol biosynthesis Peter T Clayton Functions of cholesterol Studies with labelled cholesterol indicate that, Sterols are important constituents of the cell although as much as 20% of fetal cholesterol membranes of most eukaryotic cells. The cell may be derived from the mother at the end of membranes of terrestrial vertebrates, including the first trimester, very little maternal man, contain a single major sterol species— cholesterol enters the fetal brain.56 If the cholesterol. Cholesterol is found particularly in mother is given labelled glucose, the label does external cellular membranes (plasma mem- appear in fetal brain cholesterol and glucose is branes) and in the layers that make up the thought to be the most important fuel for de myelin sheaths in the central and peripheral novo cholesterol synthesis in the fetal brain. In nervous systems. In plasma membranes, the postnatal life, a high cholesterol diet will lead to cholesterol molecules are intercalated between reduced synthesis of cholesterol in the liver. the phospholipid molecules of each monolayer This occurs principally as a result of inhibition and reduce the movement of their acyl chains of the rate limiting step, 3-hydroxy-3-methyl- (reduced “membrane fluidity”). Sterols also CoA (HMG-CoA) reductase, by cholesterol. exert a direct eVect on proteins in the In extrahepatic tissues, the uptake of lipopro- membrane. For example, the function of the tein cholesterol switches oV cholesterol synthe- human red cell hexose transporter is pro- sis in the same way. Experiments in rodents foundly aVected by the content of cholesterol with labelled cholesterol have suggested that in the membrane and this cannot be related to very little lipoprotein cholesterol enters the changes in fluidity.1 It has been discovered brain,5 but there are at least some brain cells recently that cholesterol has important interac- (microvascular endothelial cells, glial cells) tions with proteins which control embryonic which, in culture, respond to lipoprotein in the development—the hedgehog proteins.2 During medium with a reduction in de novo biosynthesis, these proteins catalyse their own cholesterol synthesis.78 cleavage and the subsequent attachment of cholesterol to the amino terminal domain. This Biosynthesis of cholesterol http://adc.bmj.com/ has a profound eVect on the range of action of Cholesterol is synthesised from acetyl-CoA. In 34 these signalling molecules. In the mouse, the the brain this is derived largely from glucose, absence of a functional gene for one of the but in other tissues fatty acids and other fuels hedgehog proteins (sonic hedgehog) results in contribute. Figures 1 and 2 show a simplified multiple malformations including holoprosen- version of the pathway. Until recently, the pre- 2 cephaly. Holoprosencephaly in mice can also vailing view has been that the reactions take be caused by giving them an inhibitor of place in the cytoplasm or endoplasmic reticu- cholesterol synthesis, AY9944. In addition to lum, but there is now accumulating evidence to on October 1, 2021 by guest. Protected copyright. its functions in cell membranes and in suggest that the early steps in the pathway at development, cholesterol acts as the precursor least occur in the peroxisomes.9 The early steps for the steroid hormones and bile acids. The in the pathway are also required for the synthe- bile acids, in turn, are necessary for eYcient sis of non-sterol isoprenes—isopentenyl- absorption of dietary lipids, including tRNAs, dolichol, ubiquinone, and haem A. cholesterol and the fat soluble vitamins. The isopentenyl groups in tRNAs are thought Given these functions of cholesterol, it is not to be important in stabilising codon-anticodon surprising that disorders of cholesterol biosyn- iteraction, thus preventing misreading of the thesis can lead to syndromes featuring major genetic code during protein synthesis. Dolichol malformations, low maternal oestriol concen- is required for the synthesis of glycoproteins, trations, failure of development of male exter- and ubiquinone and haem A are important nal genitalia due to testosterone deficiency, and components of the mitochondrial respiratory Biochemistry Unit, mental retardation associated with hypomyeli- chain. Institute of Child nation of the central nervous system. The conversion of lanosterol to cholesterol Health and Metabolic in the later stages of the pathway probably Unit, Great Ormond Sources of cholesterol occurs via two routes: in one, the Kandutsch- Street Hospital for Children, London The cholesterol present in a particular tissue Russell pathway, the immediate precursor of has either been synthesised de novo in the cells cholesterol is 7-dehydrocholesterol; in the sec- Correspondence to: of that tissue, or was derived from circulating ond pathway, the immediate precursor of Dr Peter T Clayton, lipoprotein cholesterol. For the organism as a cholesterol is desmosterol. It is thought that Biochemistry Unit, Institute of Child Health, 30 Guilford whole the two possible sources are synthesis these pathways may be independently regu- Street, London WC1N 1EH. and diet (or placental transfer in the fetus). lated but that they share many enzymes and a 186 Clayton Glucose num are unremarkable. The diagnosis is made Fatty acids by analysing organic acids in urine by gas Arch Dis Child: first published as 10.1136/adc.78.2.185 on 1 February 1998. Downloaded from Acetyl-CoA chromatography-mass spectrometry. This can Leucine be followed up by measuring the activity of HMG-CoA mevalonate kinase in cultured skin fibroblasts. Prenatal diagnosis has been achieved by – HMG-CoA reductase measurement of mevalonic acid in amniotic Mevalonic acid fluid and by measurement of mevalonate Mevalonate kinase kinase activity in amniocytes and chorionic vil- lus samples. Isopentenyl- Isopentenyl- The pathogenesis of mevalonic aciduria is pyrophosphate tRNA's not well understood. Accumulation of mevalonic acid may have some important eVects, but it is likely that deficiency of cholesterol and Farnesylpyrophosphate other products of the biosynthetic pathway play a part. Cholesterol supplementation has been Dolichol attempted but led to worsening diarrhoea and Squalene general malaise. A cocktail of cholesterol, urso- Haem A deoxycholic acid, ubiquinone, and vitamin E Lanosterol also failed to lead to detectable clinical Ubiquinone improvement. Suppression of mevalonic acid production by the use of the HMG-CoA reductase inhibitor, lovastatin, has also been 7-Dehydro- tried, but the trials had to be aborted because Desmosterol cholesterol of the development of severe clinical crises with fever, acute myopathy, worsening ataxia, diar- Steroid hormones Cholesterol Bile acids rhoea, and vomiting. Steroids have been used during acute crises. Prednisone (2 mg/kg/day) Figure 1 Pathway for the synthesis of cholesterol and led to dramatic improvement in symptoms, and non-sterol isoprenes. HMG-CoA reductase is the rate limiting step and the major site of feedback inhibition. there was a suggestion that growth and Mevalonic aciduria is caused by a defect in mevalonate psychomotor development may also be im- kinase. proved by intermittent steroid treatment. deficiency of one of these enzymes will seriously disrupt cholesterol synthesis. A number of the reactions require the participa- PEROXISOMAL DISORDERS Patients with disorders of peroxisome biogen- tion of a sterol carrier protein. esis, for example Zellweger’s syndrome and infantile Refsum’s disease, often have low Disorders aVecting the synthesis of plasma cholesterol concentration. There are lanosterol from HMG-CoA probably multiple reasons for this. The peroxi- http://adc.bmj.com/ MEVALONIC ACIDURIA somal contribution to cholesterol synthesis Mevalonic aciduria (mevalonate kinase defi- may be impaired by the absence of the ciency) was the first disorder of cholesterol organelle and by low concentrations of sterol- synthesis to be recognised, and approximately carrier protein 2. There is probably also 15 patients have been reported.10–12 The disor- malabsorption of cholesterol due to defective der is characterised by developmental delay, bile acid secretion. These patients often have failure to thrive, hypotonia, ataxia, hepato- cirrhosis and this too may be associated with splenomegaly, cataracts, lymphadenopathy, low plasma cholesterol. on October 1, 2021 by guest. Protected copyright. anaemia, myopathy, and enteropathy with fat malabsorption. In addition, many patients have Disorders aVecting the conversion of recurrent febrile crises accompanied by vomit- lanosterol to cholesterol ing, diarrhoea, an increased white cell count SMITH-LEMLI-OPITZ SYNDROME and erythrocyte sedimentation rate, and, in Smith-Lemli-Opitz (SLO) syndrome was first some cases, arthralgia, oedema, and a morbilli- described in 1964 as a syndrome of mental form rash. The dysmorphic features which retardation and multiple malformations. The have been described include microcephaly, biochemical basis became apparent when Tint dolicocephaly, a large fontanelle, a triangular and coworkers discovered that plasma and tis- facies with down slanted eyes and long sue samples from these patients contained eyelashes and low set, posteriorally rotated reduced amounts of cholesterol and vastly ears. Mild cases exist in which the only abnor- increased amounts of 7-dehydrocholesterol mal features include

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