Galactosylceramidase. (glucocerebroside)

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1 Table 10.1 Enzyme deficiencies and accumulating lipids in the main sphingolipidoses. Disease OMIM Clinical features Major lipid accumulation Enzyme defect Gene number affected Farber lipogranulomatosis (Farber disease) Generalized gangliosidosis (GM 1 gangliosidosis) Very early hoarseness, dermatitis, skeletal deformation, mental retardation, death usually before 2 years (Type I) (Type II) (Type III) Gaucher diease (Type I) (Type II) (Type III). Krabbe disease (globoid cell leukodystrophy) Metachromatic leukodystrophy (two forms) Niemann-Pick disease Types A and B Type I is infantile, severe with mental retardation, liver enlargement, skeletal deformities, red spot in retina; Type II is late-infantile/juvenile, Type III adult/chronic. Spleen and liver enlargement, erosion of long bones and pelvis; Types II and III involve nerve damage also; usually diagnosed in childhood but may be later Mental retardation, almost total absence of myelin, globoid bodies in white matter of brain; usual presentation by 6 months, death by 2 years Motor symptoms, rigidity, mental deterioration, and sometimes convulsions, onset in second year of life and death usually before 5 years; there are also later-onset forms including adult with slower progression (Type A) (Type B) As Type C (below) but ranging from a severe infantile form with neurologic degeneration and death by 3 years (type A) to a later-onset non-neurologic form (type B) compatible with survival into adulthood. Niemann-Pick disease Type C Usual onset 2-4 years of age. Neurologic abnormalities (ataxia, seizures, loss of speech), spasticity, dementia, psychiatric manifestations. Ceramide Acid ceramidase ASAH1 Ganglioside GM 1 (monosialotetrahexosylganglioside) Glucosylceramide (glucocerebroside) Galactocerebroside Galactosphingosulphatides Sphingomyelin Cholesterol (various cellular locations) and glycosphingolipids (in lysosomes) β-galactosidase-1 Acid beta-glucosidase (glucocerebrosidase) (cleaves the betaglucosidic linkage of glycosylceramide) Galactosylceramidase (Galactocerebrosidase) Aryl sulphatase A (hydrolyzes cerebroside sulphate) Sphingomyelin phosphodiesterase-1 (acid sphingomyelinase). Niemann-Pick disease, type C1, a sterol transporter (related to NPC1L1; see Box 7.2) GLB1 GBA GALC ARSA SMPD1 NPC1 (95% of cases) NPC2 (5% of cases) (continued ) 1

2 Table 10.1 (Continued ) Disease OMIM Clinical features Major lipid accumulation Enzyme defect Gene number affected Tay-Sachs disease Developmental retardation, paralysis, dementia and blindness; death in the second or third year. There are subtypes with more or less rapid onset. Ganglioside GM 2 (a structural variant of GM 1 ) (both are monosialotetrahexosylgangliosides) α-subunit of Hexosaminidase A Other GM Similar phenotype to Tay-Sachs Sandhoff disease: gangliosidoses disease β-subunit of Hexosaminidase A AB variant: GM2A activator protein Fabry disease (also Reddish purple skin rash, Gal-Gal-Glu-ceramide α-galactosidase A called Anderson- kidney failure, pain in lower (globotriaosylceramide) Fabry disease) extremities, one variant has cardiac disease, often seen in adulthood and may be slowlyprogressing. HEXA HEXB GM2A GLA OMIM: Online Mendelian Inheritance in Man ( and see text). Note that Niemann-Pick disease Type C is not strictly a disorder of sphingolipid catabolism, but that there is a secondary accumulation of sphingolipids. Table based on, and updated from EF Neufeld (1991) Lysosomal storage diseases. Annu Rev Biochem 60: and M Eckhardt (2010) Pathology and current treatment of neurodegenerative sphingolipidoses. Neuromol Med 12: See Chapter 2 for more on structures of lipids involved and Chapter 4 for more on their metabolism. 2

3 Table 10.2 Inborn errors of fatty acid oxidation. System affected Disease and enzyme deficiency OMIM number Gene affected Mitochondrial fatty acid transport Mitochondrial fatty acid oxidation Peroxisomal fatty acid oxidation Systemic carnitine deficiency (resulting from a defect in carnitine transport SLC22A5 into muscle cells through mutation in the transporter). CPT-1A (liver-specific) deficiency; deficiencies in CPT-1B (muscle type) and CPT1A CPT-1C (brain type) have not been reported. CPT-2 deficiency (infantile), (adult form) CPT2 VLCAD deficiency ACADVL MCAD deficiency (may be homozygous) ACADM SCAD deficiency ACADS LCHAD deficiency HADHA Mitochondrial trifunctional protein deficiency may be caused by mutations HADHA (α-subunit) in the α-subunit (includes LCHAD activity) or the β-subunit (LCKAT activity) HADHB (β-subunit) Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy); ABCD1 deficiency of ABCD1 Acyl-CoA oxidase deficiency ACOX1 Phytanoyl-CoA hydroxylase deficiency, Refsum disease PHYH There are more than 30 defects identified in the pathway of fatty acid oxidation, and this table is representative of the steps affected rather than exhaustive. See Further reading for more information and Section for details of FA oxidation. Based partly on P Rinaldo, D Matern & MJ Bennett (2002) Fatty acid oxidation disorders, Annu Rev Physiol 64: ; RJA Wanders, J Komen & S Kemp (2011) Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans. FEBS J 278: ABCD1, an ATP-binding cassette family transporter: see Section for further information on this family; CPT, carnitine palmitoyltransferase; LCHAD, long-chain 3-hydroxyacylacyl-CoA dehydrogenase; LCKAT, long-chain 3-ketothiolase; MCAD, medium-chain acyl-coa dehydrogenase; SCAD, short-chain acyl-coa dehydrogenase; VLCAD, very long-chain acyl-coa dehydrogenase. 3

4 Table 10.3 Some effects of platelet activating factor (PAF) in different cells/tissues. Cell/tissue Effect Implications Platelet Degranulation, aggregation Amine release, coronary thrombosis Neutrophil and other cells of the Chemotaxis, aggregation, superoxide generation; enhances Antibacterial activity immune system cytokine production Alveolar macrophage Respiratory bursts, superoxide generation Antibacterial activity Liver Inositide turnover, stimulationof glycogen breakdown Overall control of activity Hepatocytes, neurons Induces apoptosis; but in other cell types, e.g. epidermal cells, may be anti-apoptotic Removal of damaged cells, e.g. in alcoholic hepatitis. Exocrine secretory glands Similar effects to acetylcholine Overall control of activity Leukaemic cells Specific cytotoxicity towards the cells Treatment? Vascular permeability Mimics acute and chronic inflammation Pathogenesis of psoriasis? Lungs Increases airway and pulmonary oedema; decreases compliance Asthma and other respiratory conditions Tumours, Endothelial cells Enhanced angiogenesis and vascular remodelling Could contribute towards tumour growth and spread 4

5 Table 10.4 Composition of alveolar surfactant. (% w/w) Human Rabbit Rat Total protein Total lipid (% w/w of total lipid) Phosphatidylcholine (dipalmitoylphosphatidylcholine) (68) (63) (82) Phosphatidylglycerol Sphingomyelin Other phospholipids Cholesterol (free and esterified) Other lipids Percentage of phosphatidylcholine. 5

6 Table 10.5 Some genetic causes of lipodystrophy. Condition OMIM number Characteristics Defect Gene affected Congenital generalized lipodystrophy, or Berardinelli- Seip congenital lipodystrophy (various subtypes as below) Near absence of adipose tissue from birth or early infancy and severe insulin resistance. Altered glucose tolerance or (usually) diabetes, and hypertriacylglycerolaemia. Type acylglycerol-3-phosphate O-acyltransferase-2, involved in triacylglycerol synthesis (Section 4.1.1) Type The most severe form: patients are born Seipin, a protein named after the without any adipose tissue. (In the other condition, involved in lipid droplet subtypes, at least mechanical adipose formation in adipocytes. depots, in joints, are preserved.) Type Caveolin 1, a scaffolding protein involved in membrane function (Section 5.3.3). Type Includes muscular dystrophy Polymerase I and transcript release factor (hence name of gene) but this protein, also called cavin, also plays a critical role in the formation of caveolae and the stabilization of caveolins. Familial partial lipodystrophy Gradual loss of peripheral adipose tissue (FPLD) (various types as below) especially on the limbs and buttocks with preservation of subcutaneous fat on the trunk; often starts to become apparent around puberty. FPLD Type 2, Dunnigan type The commonest form. Mutations Lamin A/C is a member of the family of lipodystrophy elsewhere in the same gene cause lamin proteins involved in nuclear muscular dystrophy. Heterozygous stability. condition. FPLD Type The next most common form. Severe PPAR -γ (Section 7.3.2) is a key regulator insulin resistance. Heterozygous of adipocyte differentiation. condition. FPLD Type Rare cause of FPLD. Heterozygous Perilipin 1, a lipid droplet-associated condition. protein involved in adipocyte lipolysis (Box 9.1). FPLD Type One patient described. Adipocytes in Cell-death-inducing DNA fragmentation affected patient have multilocular rather factor a-like effector c (CIDEC), a lipid than unilocular lipid droplets. droplet protein. AKT2 mutations Not Very rare cause of severe insulin Akt1 and Akt2 are protein serine/ listed resistance, diabetes and lipodystrophy. threonine kinases, also known as protein Heterozygous condition. kinase B, involved in insulin signalling. CAV1 mutations Not Atypical partial lipodystrophy with Caveolin 1, mutations of which may also listed hypertriacylglycerolaemia; only cause generalized lipodystrophy (see described in small number of patients. above; see also Section for Fat loss from upper body only. description of caveolins). Heterozygous condition. AGPAT2 BSCL2 CAV1 PTRF LMNA PPARG PLIN1 CIDEC AKT2 CAV1 OMIM: Online Mendelian Inheritance in Man ( and see Section 10.1). PPAR-γ, peroxisome proliferator-activated receptor-γ. Note: FPLD Type 1, or Kobberling-type lipodystrophy, does not have a defined genetic cause. The classification of FPLD sub-types here is based on OMIM. Garg (2011) in Further reading numbers them differently. Conditions noted as heterozygous are inherited inanautosomaldominantmanner; othersare autosomal recessive (i.e. manifest inthe homozygousform). 6

7 Table 10.6 The classification of hyperlipidaemias according to phenotype. Type Serum cholesterol Serum triacylglycerol Particles accumulating Usual underlying defect Treatment I Chylomicrons Lipoprotein lipase deficiency; apolipoprotein CII deficiency IIa ++ N LDL LDL receptor defect or LDL overproduction IIb VLDL, LDL VLDL or LDL overproduction or impaired clearance III + ++ Chylomicronand Impaired remnant removal; may be due VLDL- to particular isoform of apolipoprotein remnants E, or apo-e deficiency IV N or + ++ VLDL VLDL overproduction or clearance defect V Chylomicrons, Lipoprotein lipase defect (not complete VLDL and absence) or apolipoprotein CII remnants deficiency Low-fat diet; medium-chain triacylglycerols to replace long-chain fatty acids Reduce dietary saturated fat and cholesterol; resins; statin drugs (HMGCoA reductase inhibitors) Reduce dietary saturated fat and cholesterol; reduce weight; fibrate drugs (PPAR-α activators); statins Reduce dietary saturated fat and cholesterol; fibrates; statins Reduce weight if obese, reduce alcohol intake; n-3 PUFA supplementation; fibrates This is known as the Fredrickson classification. N, normal; +, mildly raised; ++, moderately raised; +++, severely raised. Resins are nonabsorbed compounds that bind bile salts and cholesterol in the gastrointestinal tract so that they are excreted (see Section 7.1.2). 7

8 Table 10.7 Inborn errors of lipoprotein metabolism. Disease and enzyme deficiency Characteristics OMIM number Gene affected Conditions raising lipoprotein concentrations Familial hypercholesterolaemia (LDL-receptor deficiency) Familial combined hyperlipidaemia Lipoprotein lipase deficiency or familial chylomicronaemia syndrome (Fredrickson Type I hyperlipoproteinaemia) Sitosterolaemia Heterozygous form leads to isolated raised serum cholesterol concentration (Fredrickson Type IIa) and, if not recognized and treated, often myocardial infarction in early middle-age. It is very readily treated with statin drugs (inhibitors of HMG-CoA reductase: Section 7.3.1), and adequately-treated patients have normal life expectancy. Elevation of both cholesterol and TAG concentrations in serum in a variable fashion. Accumulation of chylomicrons in the plasma gives creamy appearance (reflecting the normal role of LPL in hydrolysing or clearing chylomicron-triacylglycerols: Section 7.2.5). In the heterozygous state there is sufficient LPL activity for almost normal triacylglycerol clearance but carriers may display features of familial combined hyperlipidaemia. Clinical manifestations similar to familial hypercholesterolaemia but with normal or moderately elevated serum cholesterol concentrations. Plant sterol concentrations in blood are markedly elevated LDLR Heterogeneous: see text LPL ABCG5 or ABCG8 Conditions resulting in lower lipoprotein concentrations Chylomicron retention disease or Anderson Severe fat malabsorption and failure to thrive in infancy. (or Anderson s) disease Deficiency of fat-soluble vitamins, low serum cholesterol concentrations, and a selective absence of chylomicrons from blood. Accumulation of chylomicron-like particles in membrane-bound compartments of enterocytes, which contain large cytosolic lipid droplets. Abetalipoproteinaemia Defect in microsomal triacylglycerol transfer protein which plays a critical role in VLDL assembly (Sections 5.6.2, and Fig. 7.5). There may be signs of fat malabsorption, and neurological and visual impairment. A characteristic finding is abnormally shaped red blood cells (often star-shaped) reflecting abnormal membrane phospholipid composition, secondary to the changes in lipoprotein concentration and composition. Tangier disease Very low circulating high-density lipoprotein (HDL)-cholesterol concentrations. Clinically, a peculiar and distinguishing feature is large orange-yellow tonsils. In the absence of normal ABCA1-mediated cholesterol efflux, cholesterol-laden macrophages accumulate in lymphoid tissues such as the tonsils, and since their lipids are derived ultimately from the diet, they include fat-soluble pigments such as β-carotene. Lecithin-cholesterol acyltransferase deficiency Clinical manifestation differs according to the exact nature of (one variant called fish-eye disease) the mutation. Fish-eye disease is so-called because of corneal opacities. Despite low HDL-cholesterol concentrations (see Section below), patients do not seem to have increased risk of CHD SAR1B MTTP ABCA LCAT and OMIM: Online Mendelian Inheritance in Man ( and see Section 10.1). 8

9 Table 10.8 Features of the atherogenic lipoprotein phenotype. Feature Hypertriacylglycerolaemia (often called hypertriglyceridaemia) Low serum HDL-cholesterol concentration Small, dense LDL particles Hyperapobetalipoproteinaemia (high concentration of apob-100 in serum) Insulin resistance Comment May by relatively mild, but usually is more marked after meals Reflects impairment of triacylglycerol-rich lipoprotein metabolism Total LDL-cholesterol concentration may be normal, hence number of particles must be increased Reflects increased number of LDL particles, as above These features are often associated with impaired action of insulin on metabolic processes 9

METABOLISM OF ACYLGLYCEROLS AND SPHINGOLIPDS. Ben S. Ashok MSc.,FAGE.,PhD., Dept. of Biochemistry

METABOLISM OF ACYLGLYCEROLS AND SPHINGOLIPDS Ben S. Ashok MSc.,FAGE.,PhD., Dept. of Biochemistry STORAGE AND MEMBRANE LIPIDS STORAGE LIPIDS Mainly as triacylglycerols (triglycerides) in adipose cells Constitute