Are HDL genes and their products targets for therapy?
Commentary on HDL therapies
Are high-density lipoprotein genes and their products targets for therapy?
News - Mar. 13, 2011Cited from: Motazacker, M et al Current Opinion in Lipidology 2010, 21:157–158
Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased cardiovascular disease (CVD). Along this and multiple other lines, many investigators work on methods to raise HDL-C levels to decrease atherosclerosis. Loss of function mutations in genes have provided insight to develop drugs to target HDL metabolism such as cholesteryl ester transfer protein inhibitors and ATP-binding cassette transporter A1 agonists of which the effects are currently investigated.
This commentary focuses on recent data on other potential targets for intervention. Hepatic lipase encoded by LIPC hydrolyses phospholipids and triglycerides in small lipoproteins. A recent study confirmed that hepatic lipase deficiency causes hyper-a-lipoproteinemia [1] whereas genetic association studies have shown that hepatic lipase tagging single nucleotide polymorphisms (SNPs) are associated with HDL-C [2] but also intermediate-density lipoprotein cholesterol (IDL-C) concentration [3] although genderspecific effects are also reported [4,5]. Paradoxically, a hepatic lipase promoter variant, associated with HDL-C, was not associated with subclinical measures of atherosclerosis [4]. In line, this same mutation and a structural hepatic lipase variant, both associated with HDL-C levels, were also shown to have no effect on risk of ischemic heart and cerebrovascular disease [6]. Endothelial lipase encoded by LIPG affects HDL metabolism through lipolysis of HDL phospholipids. Genetic association studies have previously established a role for endothelial lipase in human HDL metabolism but convincing evidence came from studying nonsynonymous mutations in endothelial lipase [7]. Endothelial lipase was furthermore shown to mediate cellular HDL uptake [8] and to promote apolipoprotein A-I-mediated cholesterol efflux [9]. Endothelial lipase-mediated remodeling of HDL was also shown to be dependent of hepatic scavenger receptor class B type 1 (SR-BI)-mediated uptake of cholesteryl ester [10]. To date, there are no data showing that genetic variation at the LIPC locus has an effect on atherosclerosis.
In 2008, genome-wide association studies (GWAS) identified a SNP near the GALNT2 locus that was associated with plasma HDL-C levels but not with CVD. Very recently, it has been demonstrated that modulation of hepatic GALNT2 expression has a direct impact on HDL-C levels in mice [11] thereby directly supporting the hypothesis that N-acetylgalactosaminyltransferase 2,
an enzyme that regulates O-linked glycosylation of proteins, plays a direct role in HDL metabolism. In two other studies, GALNT2 variation was associated with plasma triglycerides in Japanese [12] and low-density lipoprotein cholesterol (LDL-C) in Malayan [13] but not with CVD [13]. SR-BI encoded by SCARB1 is a receptor that mediates the selective uptake of HDL-C by the liver and steroidogenic tissues. Previous studies have shown that SCARB1 SNPs are associated with HDL-C levels, but a recent study showed that one out of the 43 tagging SNPs at the SCARB1 locus was associated with subclinical measures of atherosclerosis and that this effect was independent of lipids [14]. This year, farnesoid X receptor (FXR)-mediated upregulation of hepatic SR-B1 was also shown to cause hypocholesterolemia and increased reverse cholesterol transport [15]. On the other hand, hepatic SR-BI expression was shown to be linked to very low density lipoprotein (VLDL) production in mice [16] but an inhibitor of SR-BI was shown to increase HDL-C without effects on VLDL/LDL cholesterol levels in humans. In mice, the same compound had positive
effects on atherosclerosis but its effects in humans remain to be studied [17]. Overall, evidence that the above genes affect atherosclerosis in the anticipated direction is scarce. In addition, GWAS studies have shown that SNPs in the proximity of HDL genes are associated with plasma HDL-C levels but not with CVD [18]. This in itself does not provide a convincing basis to target these genes or their products to decrease CVD. In our opinion, however, the atherosclerotic process in individuals with genetically determined high or low HDL-C cannot be directly compared with the possible impact of pharmaceutical intervention in HDL pathways in patients with established CVD. To assessthis impact, large randomized placebo-controlled trials are warranted.
Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased cardiovascular disease (CVD). Along this and multiple other lines, many investigators work on methods to raise HDL-C levels to decrease atherosclerosis. Loss of function mutations in genes have provided insight to develop drugs to target HDL metabolism such as cholesteryl ester transfer protein inhibitors and ATP-binding cassette transporter A1 agonists of which the effects are currently investigated.
This commentary focuses on recent data on other potential targets for intervention. Hepatic lipase encoded by LIPC hydrolyses phospholipids and triglycerides in small lipoproteins. A recent study confirmed that hepatic lipase deficiency causes hyper-a-lipoproteinemia [1] whereas genetic association studies have shown that hepatic lipase tagging single nucleotide polymorphisms (SNPs) are associated with HDL-C [2] but also intermediate-density lipoprotein cholesterol (IDL-C) concentration [3] although genderspecific effects are also reported [4,5]. Paradoxically, a hepatic lipase promoter variant, associated with HDL-C, was not associated with subclinical measures of atherosclerosis [4]. In line, this same mutation and a structural hepatic lipase variant, both associated with HDL-C levels, were also shown to have no effect on risk of ischemic heart and cerebrovascular disease [6]. Endothelial lipase encoded by LIPG affects HDL metabolism through lipolysis of HDL phospholipids. Genetic association studies have previously established a role for endothelial lipase in human HDL metabolism but convincing evidence came from studying nonsynonymous mutations in endothelial lipase [7]. Endothelial lipase was furthermore shown to mediate cellular HDL uptake [8] and to promote apolipoprotein A-I-mediated cholesterol efflux [9]. Endothelial lipase-mediated remodeling of HDL was also shown to be dependent of hepatic scavenger receptor class B type 1 (SR-BI)-mediated uptake of cholesteryl ester [10]. To date, there are no data showing that genetic variation at the LIPC locus has an effect on atherosclerosis.
In 2008, genome-wide association studies (GWAS) identified a SNP near the GALNT2 locus that was associated with plasma HDL-C levels but not with CVD. Very recently, it has been demonstrated that modulation of hepatic GALNT2 expression has a direct impact on HDL-C levels in mice [11] thereby directly supporting the hypothesis that N-acetylgalactosaminyltransferase 2,
an enzyme that regulates O-linked glycosylation of proteins, plays a direct role in HDL metabolism. In two other studies, GALNT2 variation was associated with plasma triglycerides in Japanese [12] and low-density lipoprotein cholesterol (LDL-C) in Malayan [13] but not with CVD [13]. SR-BI encoded by SCARB1 is a receptor that mediates the selective uptake of HDL-C by the liver and steroidogenic tissues. Previous studies have shown that SCARB1 SNPs are associated with HDL-C levels, but a recent study showed that one out of the 43 tagging SNPs at the SCARB1 locus was associated with subclinical measures of atherosclerosis and that this effect was independent of lipids [14]. This year, farnesoid X receptor (FXR)-mediated upregulation of hepatic SR-B1 was also shown to cause hypocholesterolemia and increased reverse cholesterol transport [15]. On the other hand, hepatic SR-BI expression was shown to be linked to very low density lipoprotein (VLDL) production in mice [16] but an inhibitor of SR-BI was shown to increase HDL-C without effects on VLDL/LDL cholesterol levels in humans. In mice, the same compound had positive
effects on atherosclerosis but its effects in humans remain to be studied [17]. Overall, evidence that the above genes affect atherosclerosis in the anticipated direction is scarce. In addition, GWAS studies have shown that SNPs in the proximity of HDL genes are associated with plasma HDL-C levels but not with CVD [18]. This in itself does not provide a convincing basis to target these genes or their products to decrease CVD. In our opinion, however, the atherosclerotic process in individuals with genetically determined high or low HDL-C cannot be directly compared with the possible impact of pharmaceutical intervention in HDL pathways in patients with established CVD. To assessthis impact, large randomized placebo-controlled trials are warranted.
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