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Trends in Endocrinology and Metabolism:... Jan 2021Lipoprotein lipase (LPL) is one of the most important factors in systemic lipid partitioning and metabolism. It mediates intravascular hydrolysis of triglycerides packed... (Review)
Review
Lipoprotein lipase (LPL) is one of the most important factors in systemic lipid partitioning and metabolism. It mediates intravascular hydrolysis of triglycerides packed in lipoproteins such as chylomicrons and very-low-density lipoprotein (VLDL). Since its initial discovery in the 1940s, its biology and pathophysiological significance have been well characterized. Nonetheless, several studies in the past decade, with recent delineation of LPL crystal structure and the discovery of several new regulators such as angiopoietin-like proteins (ANGPTLs), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1) and Sel-1 suppressor of Lin-12-like 1 (SEL1L), have completely transformed our understanding of LPL biology.
Topics: Animals; Endoplasmic Reticulum; Humans; Hyperlipidemias; Lipoprotein Lipase; Receptors, Lipoprotein; Triglycerides
PubMed: 33277156
DOI: 10.1016/j.tem.2020.11.005 -
Journal of Physiology and Pharmacology... Jun 2022Endothelial lipase is synthetized almost exclusively in endothelial cells and then fixed on the luminal surface of the endothelium by means of heparan sulphate... (Review)
Review
Endothelial lipase is synthetized almost exclusively in endothelial cells and then fixed on the luminal surface of the endothelium by means of heparan sulphate proteoglycans. The enzyme is expressed in the endothelium of nearly all tissues and the degree of expression is higher in richly vascularized tissues than in the less vascularized ones. The endothelial lipase expression in tissues is upregulated by shear and cyclic stress, angiotensin II and hypertension. The plasma enzyme level is elevated by pro-inflammatory cytokines, in metabolic syndrome and obesity. Prolonged exercise reduces the plasma enzyme level in the rat. The activity of the enzyme is inhibited by: sphingomyelin, angiopoietin-like protein 3 and 4, and insulin. Endothelial lipase reduces the plasma high density lipoprotein concentration and changes its properties. The enzyme is considered to be the main regulator of the plasma high density lipoprotein concentration. The plasma endothelial lipase concentration is elevated in coronary atherosclerosis and it is inversely correlated with the plasma high density lipoprotein level. The enzyme is considered to exert mostly pro-atherogenic effects. Its action as triglyceride lipase is important in hypertriglyceridemia.
Topics: Animals; Rats; Atherosclerosis; Endothelial Cells; Lipase; Lipoprotein Lipase; Lipoproteins, HDL; Humans
PubMed: 36302529
DOI: 10.26402/jpp.2022.3.01 -
Endocrinology and Metabolism (Seoul,... Aug 2022High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein... (Review)
Review
High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hypertriglyceridemia; Lipoprotein Lipase
PubMed: 36065644
DOI: 10.3803/EnM.2022.402 -
Cell Metabolism Jul 2019Lipoprotein lipase (LPL), identified in the 1950s, has been studied intensively by biochemists, physiologists, and clinical investigators. These efforts uncovered a... (Review)
Review
Lipoprotein lipase (LPL), identified in the 1950s, has been studied intensively by biochemists, physiologists, and clinical investigators. These efforts uncovered a central role for LPL in plasma triglyceride metabolism and identified LPL mutations as a cause of hypertriglyceridemia. By the 1990s, with an outline for plasma triglyceride metabolism established, interest in triglyceride metabolism waned. In recent years, however, interest in plasma triglyceride metabolism has awakened, in part because of the discovery of new molecules governing triglyceride metabolism. One such protein-and the focus of this review-is GPIHBP1, a protein of capillary endothelial cells. GPIHBP1 is LPL's essential partner: it binds LPL and transports it to the capillary lumen; it is essential for lipoprotein margination along capillaries, allowing lipolysis to proceed; and it preserves LPL's structure and activity. Recently, GPIHBP1 was the key to solving the structure of LPL. These developments have transformed the models for intravascular triglyceride metabolism.
Topics: Animals; Endothelial Cells; Humans; Hyperlipoproteinemia Type I; Hypertriglyceridemia; Lipoprotein Lipase; Receptors, Lipoprotein
PubMed: 31269429
DOI: 10.1016/j.cmet.2019.05.023 -
Advances in Pharmacology (San Diego,... 2017In this review, we consider the biosynthetic, hydrolytic, and oxidative metabolism of the endocannabinoids anandamide and 2-arachidonoylglycerol. We describe the enzymes... (Review)
Review
In this review, we consider the biosynthetic, hydrolytic, and oxidative metabolism of the endocannabinoids anandamide and 2-arachidonoylglycerol. We describe the enzymes associated with these events and their characterization. We identify the inhibitor profile for these enzymes and the status of therapeutic exploitation, which to date has been limited to clinical trials for fatty acid amide hydrolase inhibitors. To bring the review to a close, we consider whether point block of a single enzyme is likely to be the most successful approach for therapeutic exploitation of the endocannabinoid system.
Topics: Animals; Endocannabinoids; Enzyme Inhibitors; Humans; Lipoprotein Lipase; Oxidation-Reduction; Signal Transduction; Synapses
PubMed: 28826539
DOI: 10.1016/bs.apha.2017.03.006 -
Trends in Endocrinology and Metabolism:... Jul 2016GPIHBP1, a GPI-anchored protein in capillary endothelial cells, is crucial for the lipolytic processing of triglyceride-rich lipoproteins (TRLs). GPIHBP1 shuttles... (Review)
Review
GPIHBP1, a GPI-anchored protein in capillary endothelial cells, is crucial for the lipolytic processing of triglyceride-rich lipoproteins (TRLs). GPIHBP1 shuttles lipoprotein lipase (LPL) to its site of action in the capillary lumen and is essential for the margination of TRLs along capillaries - such that lipolytic processing can proceed. GPIHBP1 also reduces the unfolding of the LPL catalytic domain, thereby stabilizing LPL catalytic activity. Many different GPIHBP1 mutations have been identified in patients with severe hypertriglyceridemia (chylomicronemia), the majority of which interfere with folding of the protein and abolish its capacity to bind and transport LPL. The discovery of GPIHBP1 has substantially revised our understanding of intravascular triglyceride metabolism but has also raised many new questions for future research.
Topics: Animals; Humans; Hypertriglyceridemia; Lipoprotein Lipase; Receptors, Lipoprotein; Triglycerides
PubMed: 27185325
DOI: 10.1016/j.tem.2016.04.013 -
International Journal of Molecular... Nov 2020Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the... (Review)
Review
Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer's disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, , and have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Lipoprotein Lipase; Lipoproteins; Macrophages; Mice; Microglia; Mutation; Structure-Activity Relationship; Triglycerides
PubMed: 33172164
DOI: 10.3390/ijms21218338 -
Annual Review of Nutrition Aug 2012Lipoprotein lipase (LPL) is rate limiting in the provision of triglyceride-rich lipoprotein-derived lipids into tissues. LPL is also present in the brain, where its... (Review)
Review
Lipoprotein lipase (LPL) is rate limiting in the provision of triglyceride-rich lipoprotein-derived lipids into tissues. LPL is also present in the brain, where its function has remained elusive. Recent evidence implicates a role of LPL in the brain in two processes: (a) the regulation of energy balance and body weight and (b) cognition. Mice with neuron-specific deletion of LPL have increases in food intake that lead to obesity, and then reductions in energy expenditure that further contribute to and sustain the phenotype. In other mice with LPL deficiency rescued from neonatal lethality by somatic gene transfer wherein LPL in the brain remains absent, altered cognition ensues. Taking into consideration data that associate LPL mutations with Alzheimer's disease, a role for LPL in learning and memory seems likely. Overall, the time is ripe for new insights into how LPL-mediated lipoprotein metabolism in the brain impacts CNS processes and systems biology.
Topics: Animals; Body Weight; Brain; Central Nervous System; Energy Metabolism; Gene Expression Regulation, Enzymologic; Humans; Learning; Lipoprotein Lipase; Memory; Nerve Tissue Proteins; Neurons; Peripheral Nervous System; Spinal Cord
PubMed: 22540257
DOI: 10.1146/annurev-nutr-071811-150703 -
International Journal of Environmental... Jan 2017In recent years, the lipoprotein lipase (LPL) polymorphism has been extensively investigated as a potential risk factor for coronary artery disease (CAD). However, the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In recent years, the lipoprotein lipase (LPL) polymorphism has been extensively investigated as a potential risk factor for coronary artery disease (CAD). However, the results of these studies have been inconsistent. Therefore, we performed this meta-analysis to explore the association between LPL polymorphism and CAD risk.
METHODS
The literature was searched from electronic databases such as Embase, China Biological Medicine Database, PubMed, Knowledge Infrastructure, and China National Web of Science by the key words "coronary artery disease", "lipoprotein lipase" and "polymorphism". All of the studies included in this manuscript met the inclusion and exclusion criteria. An odds ratio (OR) analysis using a 95% confidence interval (CI) was employed to assess the association of the LPL polymorphism with CAD susceptibility.
RESULTS
We performed a meta-analysis of 14 case-control studies including HindIII, Ser447X and PvuII polymorphism. A statistically significant increase in the risk of CAD was associated with LPL HindIII polymorphism. This included HindIII H⁺H⁺ genotype (OR = 1.28, 95% CI = 1.09-1.49, = 0.002, I² = 43%) and H⁺ allele genotype (OR = 1.27, 95% CI = 1.03-1.58, = 0.03, I² = 67%). Ser447X XX genotype (OR = 2.37, 95% CI = 1.33-4.24, = 0.004, I² = 53%) was also associated with CAD risk. However, PvuII polymorphism was found to have no significant association with CAD risk.
CONCLUSIONS
LPL HindIII polymorphism was significantly associated with the risk of CAD. For Ser447X polymorphism, it was found that only XX genotype was significantly associated with CAD risk. Furthermore, PvuII polymorphism had no significant association with CAD risk. It was considered that LPL HindIII polymorphism might serve as a potential biomarker for CAD risk.
Topics: Adult; Aged; Aged, 80 and over; Alleles; Biomarkers; Case-Control Studies; Coronary Artery Disease; Female; Genetic Predisposition to Disease; Genotype; Humans; Lipoprotein Lipase; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Risk Factors
PubMed: 28275220
DOI: 10.3390/ijerph14010084 -
Current Opinion in Clinical Nutrition... Mar 2019Lipoprotein lipase (LpL) is well known for its lipolytic action in blood lipoprotein triglyceride catabolism. This article summarizes the recent mechanistic and... (Review)
Review
PURPOSE OF REVIEW
Lipoprotein lipase (LpL) is well known for its lipolytic action in blood lipoprotein triglyceride catabolism. This article summarizes the recent mechanistic and molecular studies on elucidating the 'unconventional' roles of LpL in mediating biological events related to immune cell response and lipid transport in the pathogenesis of cardiovascular disease (CVD) and tissue degenerative disorders.
RECENT FINDINGS
Several approaches to inactivate the inhibitors that block LpL enzymatic activity have reestablished the importance of systemic LpL activity in reducing CVD risk. On the other hand, increasing evidence suggests that focal arterial expression of LpL relates to aortic macrophage levels and inflammatory processes. In the hematopoietic origin, LpL also plays a role in modulating hematopoietic stem cell proliferation and circulating blood cell levels and phenotypes. Finally, building upon the strong genetic evidence on the association with assorted brain disorders, a new era in exploring the mechanistic insights into the functions and activity of LpL in brain that impacts central nerve systems has begun.
SUMMARY
A better understanding of the molecular action of LpL will help to devise novel strategies for intervention of a number of diseases, including blood cell or metabolic disorders, as well to inhibit pathways related to CVD and tissue degenerative processes.
Topics: Cardiovascular Diseases; Humans; Lipoprotein Lipase; Triglycerides
PubMed: 30648986
DOI: 10.1097/MCO.0000000000000536