Eleni E. Zanni

Transcriptional regulatory mechanisms of the human apolipoprotein genes in vitro and in vivo.

The present review summarizes recent advances in the transcriptional regulation of the human apolipoprotein genes, focusing mostly, but not exclusively, on in-vivo studies and signaling mechanisms that affect apolipoprotein gene transcription. An attempt is made to explain how interactions of transcription factors that bind to proximal promoters and distal enhancers may bring about gene transcription. The experimental approaches used and the transcriptional regulatory mechanisms that emerge from these studies may also be applicable in other gene systems that are associated with human disease. Understanding extracellular stimuli and the specific mechanisms that underlie apolipoprotein gene transcription may in the long run allow us to selectively switch on antiatherogenic genes, and switch off proatherogenic genes. This may have beneficial effects and may confer protection from atherosclerosis to humans.

Transcriptional Regulation of the Human Apolipoprotein Genes

The transcription of eukaryotic genes is controlled by the interaction of regulatory gene sequences (promoter elements) with specific nuclear proteins (transcription factors) (1–3). The interaction of the transcription factors with the promoter elements controls: a) tissue specific gene expression (4–6); b) gene expression during differentiation and development (7,8); and c) gene expression in response to intracellular and extracellular stimuli such as hormones and metabolites (9–12).

Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer

Purpose of the review This review clarifies the functions of key proteins of the chylomicron and the HDL pathways. Recent findings Adenovirus-mediated gene transfer of several apolipoprotein (apo)E forms in mice showed that the amino-terminal 1-185 domain of apoE can direct receptor-mediated lipoprotein clearance in vivo. Clearance is mediated mainly by the LDL receptor. The carboxyl-terminal 261-299 domain of apoE induces hypertriglyceridemia, because of increased VLDL secretion, diminished lipolysis and inefficient VLDL clearance. Truncated apoE forms, including apoE2-202, have a dominant effect in remnant clearance and may have future therapeutic applications for the correction of remnant removal disorders. Permanent expression of apoE and apoA-I following adenoviral gene transfer protected mice from atherosclerosis. Functional assays, protein cross-linking, and adenovirus-mediated gene transfer of apoA-I mutants in apoA-I deficient mice showed that residues 220-231, as well as the central helices of apoA-I, participate in ATP-binding cassette transporter A1-mediated lipid efflux and HDL biogenesis. Following apoA-I gene transfer, an amino-terminal deletion mutant formed spherical α-HDL, a double amino- and carboxyl-terminal deletion mutant formed discoidal HDL, and a carboxyl-terminal deletion mutant formed only pre-β-HDL. The findings support a model of cholesterol efflux that requires direct physical interactions between apoA-I and ATP-binding cassette transporter A1, and can explain Tangier disease and other HDL deficiencies. Summary New insights are provided into the role of apoE in cholesterol and triglyceride homeostasis, and of apoA-I in the biogenesis of HDL. Clearance of the lipoprotein remnants and increase in HDL synthesis are obvious targets for therapeutic interventions.

Pleiotropic Functions of HDL Lead to Protection from Atherosclerosis and Other Diseases

High density lipoprotein (HDL) is a macromolecular complex of proteins and lipids that is produced primarily by the liver through a complex pathway that requires initially the functions of apolipoprotein A-I (apoA-I), ATP binding cassette transporter A1 (ABCA1) and lecithin:cholesterol acetyl transferase (LCAT) (Zannis et al., 2006b). Following synthesis, HDL affects the functions of the arterial wall cells through signaling mechanisms mediated by scavenger receptor class B type-I (SR-BI) and other cell surface proteins. The impetus for studying HDL has been the inverse correlation that exists between plasma HDL levels and the risk for coronary artery disease (CAD) (Gordon et al., 1989). HDL promotes cholesterol efflux (Gu et al., 2000; Nakamura et al., 2004), prevents oxidation of low density lipoprotein (LDL) (Navab et al., 2000a; Navab et al., 2000b), inhibits expression of proinflammatory cytokines by macrophages (Okura et al., 2010) as well as expression of adhesion molecules by endothelial cells (Cockerill et al., 1995; Nicholls et al,. 2005b). HDL inhibits cell apoptosis (Nofer et al., 2001) and promotes endothelial cell proliferation and migration (Seetharam et al., 2006). HDL stimulates release of nitric oxide (NO) from endothelial cells thus promoting vasodilation (Mineo et al., 2003). HDL also inhibits platelet aggregation and thrombosis (Dole et al., 2008) and has antibacterial, antiparasitic and antiviral activities (Parker et al., 1995; Singh et al., 1999; Vanhollebeke and Pays, 2010). Due to these properties HDL is thought to protect the endothelium and inhibit several steps in the cascade of events that lead to the pathogenesis of atherosclerosis and various other human diseases. This review focuses on two important aspects of contemporary HDL research. The first part considers briefly the structure of apoA-I and HDL and the key proteins that participate in the pathway of the biogenesis of HDL as well as clinical phenotypes associated with HDL abnormalities. The second part considers various physiological functions of HDL and apoA-I and the protective role of HDL against atherosclerosis and other diseases.

Regulation of ApoA-I Gene Expression and Prospects to Increase Plasma ApoA-I and HDL Levels

In humans, the apolipoprotein A-I (apoA-I) gene is expressed abundantly in liver and intestine, and to a lesser extent in other tissues. Following synthesis, apoA-I is secreted in plasma and proceeds to participate in the formation of high density lipoprotein (HDL). In the absence of apoA-I, HDL is not formed.

Role of Apolipoprotein E in Alzheimer’s Disease

Alzheimer’s Disease (AD) is a devastating disease which affects the elderly population and is associated with loss of memory (1–3). The prevalence of AD in people over 65 years of age is approximately 5–10%, and for people over 85 is approximately 50% (1). It is estimated that the current annual cost for care of AD patients is

Apolipoprotein and lipoprotein synthesis and modifications

100 billion. Furthermore, it is projected that the number of people affected by AD will increase 4-fold by the year 2030. Clearly, AD is a major public health problem.

Genetic Factors Contributing to Cardiovascular Disease that may affect Endothelial Structure and Function: The Role of Proteins involved in Lipoprotein Transport

Conventional and molecular biological approaches have defined the sites of apolipoprotein synthesis and have described intra- and extracellular apolipoprotein modifications. Topics selected for discussion in this review include new aspects of apolipoprotein synthesis and modifications, modification of apolipoprotein B byproducts of lipid oxidation, remodeling of lipoproteins by transfer of apolipoproteins and functional significance, in vivo and in vitro assembly of apolipoprotein B-containing lipoproteins, and intracellular versus extracellular assembly of high-density lipoprotein and lipoprotein-type particles.

Genetic Mutations Affecting Human Lipoproteins, Their Receptors, and Their Enzymes

Lipoproteins are macromolecular complexes of lipids and proteins which originate mainly from the liver and intestine, and are involved in the transport and redistribution of lipids in the body. The plasma lipoproteins are spherical particles with cores of nonpolar neutral lipid consisting of cholesteryl ester and triglycerides and coats of relatively polar materials consisting of phospholipid, free cholesterol, and proteins(1, 2) (Figure 1 A). The plasma lipoproteins have traditionally been grouped in four major lipoprotein classes: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). A lipoprotein class of intermediate density (IDL) found between VLDL, LDL and several subpopulations of VLDL, LDL and HDL have been described. Finally, lipoprotein particles (Lp) with defined lipid and apolipoprotein composition have also been isolated from plasma and the media of cell cultures (3, 4). The protein components of lipoproteins are called apolipoproteins and have been designated apoA-I, apoA-II, apoA-IV, apoB, apoCI, apo CII, apoCIII, apoD, and apoE (5). The lipid, apolipoprotein composition and the properties of the human plasma lipoproteins are shown in Table I.