Endothelial Lipase: Direct Evidence for a Role in HDL Metabolism
Total Page：16
File Type：pdf, Size：1020Kb
Endothelial lipase: direct evidence for a role in HDL metabolism Jonathan C. Cohen J Clin Invest. 2003;111(3):318-321. https://doi.org/10.1172/JCI17744. Commentary For the past three decades, epidemiologic studies have consistently demonstrated an inverse relationship between plasma HDL cholesterol (HDL-C) concentrations and coronary heart disease (CHD) (1). Population-based studies have provided compelling evidence that low HDL-C levels are a risk factor for CHD (2–4), and several clinical interventions that increased plasma levels of HDL-C were associated with a reduction in CHD risk (5, 6). These findings have stimulated extensive investigation into the determinants of plasma HDL-C levels. Turnover studies using radiolabeled apolipoprotein A-I, the major protein component of HDL, suggest that plasma HDL-C concentrations are highly correlated with the rate of clearance of apolipoprotein AI (7). However, the metabolic mechanisms by which HDL are catabolized have not been fully defined. Previous studies in humans with genetic deficiency of cholesteryl ester transfer protein (8), and in mice lacking the scavenger receptor BI (SR-BI) (9), have demonstrated that these proteins participate in the removal of cholesterol from HDL, while observations in individuals with mutations in hepatic lipase indicate that this enzyme hydrolyzes HDL triglycerides (10). In this issue of the JCI, reports from laboratories of Tom Quertermous (11) and Dan Rader (12) now indicate that endothelial lipase (LIPG), a newly identified member of the lipase family, catalyzes the hydrolysis of HDL phospholipids and facilitates the clearance of HDL from the circulation. Endothelial lipase was […] Find the latest version: https://jci.me/17744/pdf COMMENTARIES See the related articles beginning on pages 347 and 357. Endothelial lipase: direct evidence for a role tions of VLDL and LDL cholesterol by about 50 percent, whereas HDL-C in HDL metabolism decreased to almost zero in these ani- mals (14). These data suggested that Jonathan C. Cohen endothelial lipase may play a role in HDL catabolism. McDermott Center for Human Growth and Development, Center for Human Nutrition, To prove that endothelial lipase plays Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, a physiological role in HDL metabo- Dallas, Texas, USA lism, both groups assessed the effects of J. Clin. Invest. 111:318–321 (2003). doi:10.1172/JCI200317744. diminished endothelial lipase activity in vivo. The Quertermous group used gene targeting to inactivate Lipg in mice. For the past three decades, epidemio- this issue of the JCI, reports from labo- Lipg–/– mice were viable and fertile and logic studies have consistently demon- ratories of Tom Quertermous (11) and had no obvious defects. Plasma choles- strated an inverse relationship between Dan Rader (12) now indicate that terol and phospholipid concentrations plasma HDL cholesterol (HDL-C) con- endothelial lipase (LIPG), a newly iden- were increased by 69 percent and 52 per- centrations and coronary heart disease tified member of the lipase family, cat- cent respectively in male Lipg–/– mice. (CHD) (1). Population-based studies alyzes the hydrolysis of HDL phospho- The changes in plasma cholesterol were have provided compelling evidence that lipids and facilitates the clearance of due primarily to an increase in plasma low HDL-C levels are a risk factor for HDL from the circulation. HDL. Despite comparable increases in CHD (2–4), and several clinical inter- Endothelial lipase was initially plasma phospholipid levels, the increase ventions that increased plasma levels of cloned by both of these laboratories in plasma cholesterol levels in female HDL-C were associated with a reduc- using entirely different strategies. Lipg–/– mice was far more modest than tion in CHD risk (5, 6). These findings Quertermous and his colleagues iden- that observed in male mice. To further have stimulated extensive investigation tified endothelial lipase as a transcript evaluate the effect of varying endothelial into the determinants of plasma HDL- that was upregulated in cultured lipase activity, Quertermous also gener- C levels. Turnover studies using radiola- human umbilical vein endothelial cells ated mice expressing a human LIPG beled apolipoprotein A-I, the major pro- undergoing tube formation (13), transgene. Consistent with the findings tein component of HDL, suggest that whereas the Rader group cloned in endothelial lipase knockout mice, plasma HDL-C concentrations are high- endothelial lipase as a transcript that overexpression of LIPG resulted in mod- ly correlated with the rate of clearance of was upregulated in the human est decreases in plasma phospholipid apolipoprotein AI (7). However, the macrophage-like cell line THP-1 and cholesterol concentrations. Rader metabolic mechanisms by which HDL exposed to oxidized LDL (14). Data- and colleagues inhibited endothelial are catabolized have not been fully base searches revealed that endothelial lipase in mice by administering a poly- defined. Previous studies in humans lipase shows strong sequence similari- clonal anti-murine endothelial lipase with genetic deficiency of cholesteryl ty to lipoprotein lipase (44 percent antibody, a strategy that has been used ester transfer protein (8), and in mice identity) and hepatic lipase (41 percent previously to assess the physiological lacking the scavenger receptor BI (SR- identity), two well-characterized lipas- roles of hepatic lipase and lipoprotein BI) (9), have demonstrated that these es that function at vascular endothelial lipase. In wild-type mice, plasma choles- proteins participate in the removal of surfaces. Critical motifs associated terol and phospholipid concentrations cholesterol from HDL, while observa- with lipase activity (GXSXG and the increased by about 25 percent within 24 tions in individuals with mutations in catalytic triad S169, D193, H274), and hours of antibody administration. Inhi- hepatic lipase indicate that this enzyme with heparin binding were strongly bition of endothelial lipase activity hydrolyzes HDL triglycerides (10). In conserved (13, 14). Interestingly, in elicited more pronounced changes in contrast to both lipoprotein lipase and plasma lipid levels in hepatic Address correspondence to: Address hepatic lipase, endothelial lipase has lipase–deficient mice and in ApoAI correspondence to: Jonathan C. Cohen, little triglyceride hydrolase activity in transgenic mice. In the ApoAI trans- Center for Human Nutrition, University of vitro but instead cleaves fatty acids genic mice, antibody administration Texas Southwestern Medical Center at Dallas, from the sn-1 position of phos- was associated with a modest but statis- 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052, USA. Phone: (214) 648-4774; phatidylcholine. In in vitro assays the tically significant reduction in HDL- Fax: (214) 648-4837; E-mail: enzyme is most active on lipids pre- phospholipid turnover. [email protected]. sented in HDL, although it will release These findings suggest that the meta- Conflict of interest: The author has declared fatty acids from all classes of lipopro- bolic pathways of the two major classes that no conflict of interest exists. teins (15). Consistent with this finding, of lipoproteins, apolipoprotein B con- Nonstandard abbreviations used: HDL cholesterol (HDL-C); coronary heart disease adenovirus-mediated overexpression of taining lipoproteins and HDL, may have (CHD); scavenger receptor BI (SR-BI); endothelial lipase in LDL receptor-defi- more in common than was previously endothelial lipase (LIPG). cient mice reduced plasma concentra- recognized, and that normal lipoprotein The Journal of Clinical Investigation | February 2003 | Volume 111 | Number 3 1 Figure 1 Sequence alignment of lipoprotein lipase (lpl), hepatic lipase (hl), and endothelial lipase (el) from human (h) and pufferfish Takifugu rubripes (f). Amino acids that are identical in all three genes in both species are shaded in grey. The serine, aspartic acid, and histidine resides of the catalytic triad, as well as the lipase motif (GXSXG) are boxed. The conserved cysteine residues are denoted with closed circles. The lid domain is indicated with a sin- gle line, and the conserved heparin-binding region (BBXB) is indicated with a double line. metabolism requires the action of three removed from the circulation by recep- The high degree of sequence conser- vascular endothelial lipases with distinct tor-mediated endocytosis. Consequent- vation among the three vascular substrate specificities. The catabolic ly, patients lacking lipoprotein lipase endothelial lipases suggests that they pathway for the apolipoprotein B con- accumulate very large, triglyceride-rich arose from a common ancestor and taining lipoproteins includes two lipoproteins (16), whereas genetic defects evolved distinct substrate specificities sequential steps; lipolysis and receptor- in hepatic lipase lead to the accumula- to accommodate the full spectrum of mediated endocytosis. Nascent triglyc- tion of partially-delipidated lipoproteins circulating lipoproteins. The duplica- eride-rich lipoproteins secreted from the of intermediate density (10). Now it tion events that (presumably) gave rise liver and intestine (chylomicrons and appears that high density lipoprotein to the three lipases must have occurred very low density lipoproteins) are delipi- metabolism may also include both a early in vertebrate evolution, since the dated first by lipoprotein lipase,