Genetics of HDL regulation in humans

Abstract

Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.

Extrinsic effectors regulating genes for plasmalogen biosynthetic enzymes in HepG2 cells

“…Moreover, pitavastatin promoted the expression of HDL metabolism-associated proteins such as APOA1. It is proposed that this is probably via enhancement of PPAR expression, since APOA1 and ABCA1 expression are upregulated by PPAR agonists [37].…”

Dyslipidemia: Genetics and Role in the Metabolic Syndrome

“…Several LPL SNPs have been associated with HDL-C (Table 1) (Ahn et al, 1993;Corella et al, 2002;Holmer et al, 2000;Klos and Kullo, 2007;Klos et al, 2006;Komurcu-Bayrak et al, 2007;Lee et al, 2004;Nettleton et al, 2007;Senti et al, 2001;Wittrup et al, 1999); however, many of them are in strong linkage disequilibrium with each other (e.g., rs320, rs326, rs13702, rs10105606) (Boes et al, 2009;Heid et al, 2008). Hepatic lipase (HL; LIPC) is a glycoprotein that is synthesized by liver cells (hepatocytes) and catalyzes the hydrolysis of TG and phospholipids (Miller et al, 2003). For example, after hydrolysis of TG by LPL, VLDL particles are reduced to IDL particles and can be further hydrolyzed by HL/LIPC to LDL or taken up by the liver (Kwan et al, 2007).…”

“…Scavenger receptor class B, type 1 (SCARB1; SR-B1), which is highly expressed in liver and steroidogenic tissues (testes, ovaries, adrenal) (Cao et al, 1997), has been shown to participate in the uptake of HDL in animals by transferring cholesterol from the HDL-C particle and releasing the lipid-depleted HDL particle into the circulation (Acton et al, 1996;Miller et al, 2003). The human SCARB1 gene is located on chromosome 12 (12q24.31).…”

“…Although some common polymorphisms in LDLR have been associated with HDL-C levels (Table 1: (Costanza et al, 2005;Hegele et al, 1995;Yamada et al, 2008), their impact is likely greater on LDL-C levels (see Section 3.1). The ATP-binding cassette transporter A1 (ABCA1), which is highly expressed in the liver, steroidogenic tissues and macrophages, plays a key role in 'reverse cholesterol transport' by mediating the efflux of cholesterol and phospholipids from macrophages to the nascent lipid-free, APOA-1 HDL particle (Cavelier et al, 2006;Miller et al, 2003). The human ABCA1 gene is located on chromosome 9 (9q31.1).…”

“…Apolipoprotein A-1 (APOA1; APOA-I) is a ligand required for HDL-C binding to its receptors including SCARB1 and ABCA1 and, is an important cofactor in 'reverse cholesterol transport' (Miller et al, 2003;Remaley et al, 2001;Rigotti et al, 1997). The human APOA1 gene is located on chromosome 11 (11q23-24).…”