Promoter Variants and Variant Promoters of the Hepatic Lipase Gene

Het onderzoek beschreven in dit proefschrift werd uitgevoerd op de afdeling Biochemie Cardiovascular Research School COEUR en de afdeling interne geneeskunde van de Erasmus Universiteit te Rotterdam. 1.0 Introduction 7 1.1 Role of Hepatic lipase in lipoprotein metabolism 8 1.1.1 Hepatic lipase 8 1.1.2 Hepatic lipase and reverse cholesterol transport 10 1.1.3 Hepatic lipase and steroidogenesis 10 1.1.4 Hepatic lipase deficiency 11 1.1.5 Hepatic lipase and type 2 diabetes 14 1.2 Genetics of hepatic lipase 16 1.2.1 Lipase gene family 16 1.2.2 Genomic organisation of hepatic lipase 17 1.2.3 Regulation of hepatic lipase expression 18 1.2.3.1 Gene expression 18 1.2.3.2 5' Regulatory region of hepatic lipase 20 1.2.3.3 Transcriptional regulation of hepatic lipase 21 1.3 Scope of this thesis 22 References 23 2.0 Comparative genomics and experimental promoter analysis reveal functional liver-specific elements in mammalian hepatic lipase genes 33 3.0 Transient induction of a variant hepatic lipase messenger RNA by corticotropic hormone in rat adrenals 49 4.0 Cloning, Expression and Promoter Analysis of Hepatic Lipase Derived from Human Hyperplastic Adrenals: Evidence for Alternative Splicing 69 5.0 Human HL promoter polymorphism 83 5.1 Methods for determination of the hepatic lipase promoter genotype 85 5.2 The effect of the LIPC –514C/T polymorphism on plasma HDL levels is strongly affected by plasma triglycerides 95 5.3 Combined cholesteryl ester transfer protein and hepatic lipase gene variants associate with coronary artery disease despite increased HDL cholesterol 105 6.0 Hepatic lipase promoter activity is reduced by the C-480T and G-216A substitutions present in the common LIPC gene variant, and is increased by Upstream Stimulatory Factor 117 7.0 Sterol-regulatory-element binding protein inhibits upstream stimulatory factor-stimulated hepatic lipase gene expression 131 8.0 General discussion 143 Summary 157 Samenvatting 161 List of publications 165 Curriculum vitae 166 Dankwoord 167 Chapter 1.0 Introduction Chapter 1 8 1.1 Role of Hepatic lipase in lipoprotein metabolism 1.1.1 Hepatic lipase Hepatic lipase (HL; E.C. 3.1.1.34) is a glycoprotein with triglyceridase, phospholipase A1 and some esterase activity, but no cholesterylesterase activity. During the assembly of the HL protein the rat HL protein acquires two and the human four oligosaccharide chains. Most HL is synthesised in liver parenchymal cells and secreted into the space of Disse were it binds to heparan sulfate proteoglycans. HL activity is also present in the steroidogenic organs as adrenal glands, ovaries and testis. The HL protein is synthesised in the liver and transported via the bloodstream to these steroidegenic organs …