Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes

LPL contributes profoundly to physiologic lipoprotein metabolism and to tissue-specific substrate delivery and utilization (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar). Perturbed LPL activity affects global energy balance, insulin action, body weight maintenance, and CVD risk; the latter alluded to by contemporary human genetic studies. LPL is the pivotal rate-limiting mediator of hydrolysis of core TGs from TG-rich lipoproteins, particularly chylomicrons and VLDL (2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar). The products of LPL-mediated catalysis, such as fatty acids and monoacylglycerol, are handled differentially at local sites depending on the global hormonal and nutritional milieu, and local energy needs. For instance, in the fasted state, LPL activity in adipose tissue is suppressed, while it is increased in skeletal and cardiac muscle, shunting fatty acids away from storage and toward utilization in heavily oxidizing tissues. Conversely, after eating, LPL activity in adipose tissue is enhanced, while it is suppressed in skeletal and cardiac muscles, shunting fatty acids toward storage. Similar tissue-specific modulation of LPL activity is related to cold and exercise (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Recently, the complexity of the regulation of LPL secretion and activity has become more apparent; some insights have emerged from studying natural human genetic variants. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar); furthermore, depending on local milieu and needs, this regulation is tissue specific. At least 10 gene products govern the secretion and activity of LPL at different stages of its life cycle. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities, such as the heart, skeletal muscle, and brown and white adipose tissue. Although various factors influence LPL gene transcription (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar), much of the physiological variation in LPL activity, i.e., related to feeding-fasting cycles and exercise, appears to be driven via posttranslational mechanisms by extracellular proteins. These proteins can be divided into two main groups: the liver-derived apolipoproteins, which are products of the APOC1, APOC2, APOE, APOC3, and APOA5 genes, and the more broadly expressed angiopoietin-like (ANGPTL) proteins, specifically the products of the ANGPTL3, ANGPTL4, and ANGPTL8 genes. But even prior to regulation by apolipoproteins and ANGPTL proteins, LPL secretion and delivery to the vascular space is in the hands of other intermediaries, including products of lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) genes. In addition to classical cellular and molecular biological studies of these various proteins, studies of naturally occurring human genetic variants have helped fill in some gaps in understanding of LPL regulation. Selected information regarding genes affecting LPL discussed below is summarized in Table 1.TABLE 1Selected gene products that interact with LPL and their genetic associations with plasma lipids and CHD riskProteinGene Symbol/Chromosomal PositionEffect on LPL ActivityBiochemical PhenotypesCHD AssociationRare VariantsCommon VariantsLPLLPL/8p21.3ReferenceHmz LOF: chylomicronemiaLOF: higher TG, lower HDL-CCommon LOF: increased CHD riskHet LOF: increased risk of severe HTGGOF: lower TG, higher HDL-CCommon GOF: reduced CHD riskRare LOF Het: likely increased CHD riskRare LOF Hmz: noneLMF1LMF1/16p13.3PromotesHmz LOF: chylomicronemiaGWAS: noneCommon or rare: noneHet LOF: increased risk of severe HTGGPIHBP1GPIHBP1/8q24.3PromotesHmz LOF: chylomicronemiaGWAS: noneCommon or rare: noneHet LOF: increased risk of severe HTGapoC-IAPOC1/19q13.3InhibitsHet LOF: reduced TGGWAS: noneCommon or rare: noneapoC-IIAPOC2/19q13.3PromotesHmz LOF: chylomicronemiaGWAS: noneCommon or rare: noneHet LOF: increased risk of severe HTGapoEAPOE/19q13.3E2 isoform inhibitsHet rare LOF variants: dysbetalipoproteinemiaHmz E2 plus 2° factors: dysbetalipoproteinemiaE2 Het or Hmz without dysbetalipoproteinemia: neutral or reduced CHD riskE2 Hmz in dysbetalipoproteinemia: increased CHD riskapoC-IIIAPOC3/11q23.3InhibitsHet LOF: reduced TG, increased HDL-CGOF from candidate gene studies: higher TG, lower HDL-CCommon GOF: increased risk MR rare Het LOF: reduced CHD riskapoA-VAPOA5/11q23.3PromotesHmz LOF: chylomicronemiaLOF from GWAS: higher TG; lower HDL-CCommon Het LOF: increased CHD riskHet LOF: increased risk of severe HTGMR rare Het LOF: increased CHD riskANGPTL3ANGPTL3/1p31.3InhibitsHmz LOF: familial combined hypolipidemiaGWAS: lower LDL-C, HDL-C, TGCommon or rare: noneANGPTL4ANGPTL4/19p13.2InhibitsHet LOF: reduced TG, increased HDL-CGWAS: reduced TG, increased HDL-CCommon LOF: reduced CHD riskRare Het LOF: reduced CHD riskANGPTL8ANGPTL8/19p13.2InhibitsHet LOF: reduced TG, increased HDL-CGWAS: noneCommon or rare: noneHmz, homozygous (can also refer here to compound heterozygous, or different mutations on two alleles); Het, simple heterozygous; LOF, loss-of-function; GOF, gain-of-function; HTG, hypertriglyceridemia; HDL-C, HDL cholesterol; TG, triglyceride; GWAS, genome-wide association study results; MR, Mendelian randomization study results. Open table in a new tab Hmz, homozygous (can also refer here to compound heterozygous, or different mutations on two alleles); Het, simple heterozygous; LOF, loss-of-function; GOF, gain-of-function; HTG, hypertriglyceridemia; HDL-C, HDL cholesterol; TG, triglyceride; GWAS, genome-wide association study results; MR, Mendelian randomization study results. The central nonredundant role of basal LPL mass and activity in directing intravascular hydrolysis of TG-rich lipoproteins is underscored by the causative role of very rare homozygous loss-of-function variants in the LPL gene in patients with severe hypertriglyceridemia (essentially chylomicronemia) and increased risk of pancreatitis (5.Rodrigues R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 6.Brahm A.J. Hegele R.A. Chylomicronaemia–current diagnosis and future therapies.Nat. Rev. Endocrinol. 2015; 11: 352-362Crossref PubMed Scopus (212) Google Scholar). About 40% of patients diagnosed clinically with LPL deficiency have rare loss-of-function variants on both LPL alleles (5.Rodrigues R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar); among all patients with severe hypertriglyceridemia, ~10% have one or two probable pathogenic LPL variants. Rare instances of atherosclerosis observed in patients with complete LPL deficiency are exceptions that seem to prove the rule that severe chylomicronemia due to complete LPL deficiency is not associated with increased atherosclerosis risk (7.Benlian P. De Gennes J.L. Foubert L. Zhang H. Gagne S.E. Hayden M. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene.N. Engl. J. PubMed Scopus Google Scholar). these loss-of-function variants are in of patients with severe hypertriglyceridemia not have classical LPL deficiency J. H. R.A. et of rare variants in genes by genome-wide association study of PubMed Scopus Google Scholar). In LPL loss-of-function variants in the are associated with in plasma due in to of VLDL (5.Rodrigues R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). LPL genetic variants that TGs and lower HDL are associated with increased while a LPL that TGs and HDL has associated with from CHD G. M. et lipoprotein lipase gene lipid and a association and J. PubMed Scopus Google Scholar, and variation in ANGPTL4, and and the risk of Engl. J. 2016; PubMed Scopus Google Scholar). genetic in addition to the LPL as a of CHD that is genetic variants in the proteins on CHD risk in a with their on its intravascular activity in LPL to at the of from its of various such as or skeletal by the is a protein in the that is the and not of also of lipase and lipase M. maturation factor and role in lipase and Opin. Lipidol. PubMed Scopus Google Scholar). The of in the activity of is with its as the causative gene combined lipase deficiency M. maturation factor and role in lipase and Opin. Lipidol. PubMed Scopus Google Scholar, M. maturation factor a lipase in lipid Biophys. Acta. PubMed Scopus Google Scholar). in the maturation of not it the of lipase into and the M. maturation factor and role in lipase and Opin. Lipidol. PubMed Scopus Google Scholar, M. maturation factor a lipase in lipid Biophys. Acta. PubMed Scopus Google Scholar). Rare genetic variants in are associated with severe hypertriglyceridemia in and due to lipid from lipase deficiency M. maturation factor a lipase in lipid Biophys. Acta. PubMed Scopus Google Scholar). variants in have not reported as associated with plasma lipoproteins or atherosclerosis in genome-wide association studies in LPL is from it to the by the LPL in the space S.G. P. P. A. lipoprotein Full Text Full Text PDF PubMed Scopus Google Scholar, A. Young S.G. protein 1 and the intravascular of PubMed Scopus (33) Google and it to the it also LPL to the S.G. R. and of intravascular and 27: PubMed Scopus Google Scholar). The is to the from Young S.G. R. and of intravascular and 27: PubMed Scopus Google in the and of this The role of in LPL is by the of rare homozygous genetic variants that including its to in of LPL in the space and severe hypertriglyceridemia with is that variants are associated with plasma lipoproteins or atherosclerosis in genome-wide association studies in apolipoproteins and on LPL it its of is the of the gene on The human has combined R. G. J.L. in human Clin. PubMed Scopus Google Scholar). has reported to LPL activity by binding of LPL to the of TG-rich lipoproteins and also by LPL more to by M. P. A. G. and lipoprotein lipase activity by of the from lipid Full Text Full Text PDF PubMed Scopus Google Scholar). Recently, a rare in a of associated with a in plasma TG, with in CHD risk A. S. G. A. A. A. H. P. A. et with large on lipids and the role of and in 2016; PubMed Scopus Google Scholar). a in associated with lower body mass P. H. M. A.J. et is associated with reduced and lower plasma of and in Full Text Full Text PDF PubMed Scopus Google Scholar). is a of and HDL lipid binding and a LPL binding of the role of in lipoprotein metabolism and Full Text Full Text PDF PubMed Scopus Google Scholar). is LPL homozygous rare loss-of-function variants in to deficiency are associated with a chylomicronemia that LPL deficiency of deficiency with hypertriglyceridemia and Engl. J. PubMed Scopus Google Scholar). are in hypertriglyceridemia G. J. P. J. and levels in Full Text PDF PubMed Scopus Google Scholar); of in also to severe hypertriglyceridemia A. R. Goldberg I.J. J.L. of hypertriglyceridemia in Clin. PubMed Scopus Google Scholar), in has not Rare variants are among that are in of patients with severe hypertriglyceridemia J. R.A. M. M. 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Lipidol. 2016; 27: PubMed Scopus Google Scholar). appears to interact with LPL in at least in the and regulation of LPL levels different physiological such as exercise, and is to on the of these levels LPL as the of be by the global physiological and on the tissue. In the of the of et M. A. Young S.G. S. of lipoprotein lipase in 2016; Full Text Full Text PDF PubMed Scopus Google of of the role of affecting In and adipose tissue from and that reduced LPL protein on LPL in addition to of caused the of LPL to and in increased secretion of in LPL and that after LPL is in the physiological in adipose tissue and cold associated with in the of LPL in not in These that of by after LPL in the to the that the of with LPL can to has become due to that of rare mutations or loss-of-function variants and variation in ANGPTL4, and and the risk of Engl. J. 2016; PubMed Scopus Google Scholar, C. J. C. L. D. et variants in and risk of Engl. J. 2016; PubMed Scopus Google plasma lipid with reduced TGs and higher HDL with reduced CHD In the which is in of and has activity due to extracellular of both the protein and to be associated with reduced and increased HDL S. A. of that and PubMed Scopus Google Scholar). Although studies not this to M. J. et and on plasma and HDL and CHD PubMed Scopus Google Scholar), genetic this and variation in ANGPTL4, and and the risk of Engl. J. 2016; PubMed Scopus Google Scholar, C. J. C. L. D. et variants in and risk of Engl. J. 2016; PubMed Scopus Google Scholar). of also association the and in and CHD risk by and A. S. G. A. A. A. H. P. A. et with large on lipids and the role of and in 2016; PubMed Scopus Google Scholar). the studies by et M. A. Young S.G. S. of lipoprotein lipase in 2016; Full Text Full Text PDF PubMed Scopus Google information of to to the lipid and from CHD among of loss-of-function variants. including and is expressed in and both brown and white adipose tissue R. The a molecular 2016; PubMed Scopus Google Scholar). ANGPTL3, its is by and reduced by R. The a molecular 2016; PubMed Scopus Google Scholar); a on LPL activity has not one that ANGPTL8 its by in to LPL activity in the and skeletal R. The a molecular 2016; PubMed Scopus Google Scholar). ANGPTL8 lower associated with both reduced VLDL secretion and increased LPL activity, that ANGPTL8 a role in the and it be to fatty acids to adipose tissue storage in the J. ANGPTL8 metabolism without PubMed Scopus Google Scholar). Although the ANGPTL8 not a variants with to plasma lipids and atherosclerosis a ANGPTL8 associated with reduced and increased HDL not with from CHD A. M. et of and rare variants with lipids and in and J. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). after genetic related to and rare variants in genes that the the of human the of on the role of genetic variation affecting in the LPL in Table 1 not also its role in atherosclerosis that the is the of LPL variation on plasma lipoproteins and atherosclerosis factors that interact with LPL at its sites and or on these the associations with LPL variation and variation of one of its factors also be rare homozygous loss-of-function variants in LPL in severe hypertriglyceridemia is also in patients with rare homozygous loss-of-function variants in APOC2, and APOA5 genes, with the of the of these gene products that LPL In rare loss-of-function variants in genes that of such as APOC3, ANGPTL3, ANGPTL4, and are associated with reduced some are regarding other of the lipid such as on and HDL with variants in ANGPTL3, not with variants in the other genes. The associations with and variants be in to the of ANGPTL4, as by et M. A. Young S.G. S. of lipoprotein lipase in 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). variants are associated with the of hypertriglyceridemia in rare genetic variants this of genes are associated with in the lipid in a with the of the gene on LPL variants in LPL a are associated with reduced while a loss-of-function are associated with increased These are also in of variants in APOC3, ANGPTL3, and in genome-wide association study the of the on plasma lipids is with the of the gene on LPL genes in which rare variants severe hypertriglyceridemia, such as and APOC2, are variants that association in TGs in genome-wide association studies. the E2 isoform by is associated with the of hypertriglyceridemia in while the and ANGPTL8 genes also have variants associated with the plasma lipid in genome-wide association study homozygous rare loss-of-function variants in LPL that chylomicronemia are not associated with CHD while rare loss-of-function variants in LPL that to severe hypertriglyceridemia seem to be associated with increased CHD In variants in LPL that are associated with reduced TGs increased HDL are associated with reduced CHD while loss-of-function that are associated with increased TGs reduced HDL are associated with increased CHD Rare variants in APOC3, and are associated with CHD risk in a that is with their on TGs HDL rare variants or the E2 isoform in the of factors which has associated with CHD in studies. or rare variants in APOC2, and ANGPTL8 are not associated with CHD of their on is association or variants and CHD The associations CHD and variants in these gene products have it be that plasma TGs are not the causative and as such as the of that are not clinically or A. A. of risk of in patients with 2016; PubMed Scopus Google Scholar); different gene products with the on levels have different on such the various gene products have and on other causative plasma lipoprotein the variation in the genes the factors with LPL not on a with associations with severe hypertriglyceridemia, in plasma or CHD on the or of of the The here the and of LPL complexity has and discussed in (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). factors have other their on while some of the the of TGs as causative CHD the related that with high the here that LPL and its factors as the this association is not the that affecting of and be more in For LPL is to be and by and has to be expressed it be in the of TG-rich lipoproteins into which have more into S. Goldberg I.J. D. J.L. and lipoprotein lipase in human and PubMed Scopus Google Scholar); such a be of on plasma lipoprotein of on LPL that the new genetic as to be in the of molecular and The in the

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