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Nature Communications May 2023Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which...
Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Å resolution. This structure reveals an open hydrophobic pore adjacent to the active site residues. Using modeling, we demonstrate that this pore can accommodate an acyl chain from a triglyceride. Known LPL mutations that lead to hypertriglyceridemia localize to the end of the pore and cause defective substrate hydrolysis. The pore may provide additional substrate specificity and/or allow unidirectional acyl chain release from LPL. This structure also revises previous models on how LPL dimerizes, revealing a C-terminal to C-terminal interface. We hypothesize that this active C-terminal to C-terminal conformation is adopted by LPL when associated with lipoproteins in capillaries.
Topics: Humans; Lipoprotein Lipase; Catalytic Domain; Lipoproteins; Triglycerides; Hypertriglyceridemia
PubMed: 37142573
DOI: 10.1038/s41467-023-38243-9 -
Frontiers in Endocrinology 2022Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the () gene. To date, more than 200...
BACKGROUND
Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the () gene. To date, more than 200 mutations in the gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis.
OBJECTIVE
This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia.
METHODS
We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium.
RESULTS
Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 ± 9.46% (p<0.01) and 54.60 ± 9.03% (p<0.01), respectively, compared with the control. studies showed a substantial reduction in the expression or enzyme activity of LPL in the variants.
CONCLUSIONS
Two novel compound heterozygous variants of induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated mutant activity.
Topics: Acute Disease; Adolescent; Female; Humans; Hyperlipoproteinemia Type I; Lipoprotein Lipase; Pancreatitis; Pedigree
PubMed: 35923617
DOI: 10.3389/fendo.2022.874608 -
Molecular Metabolism Jun 2022Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around...
OBJECTIVE
Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity.
METHODS
RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-hour intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT.
RESULTS
We identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT.
CONCLUSIONS
Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health.
Topics: Adipose Tissue, Brown; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Lipoprotein Lipase; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma; Triglycerides
PubMed: 35413480
DOI: 10.1016/j.molmet.2022.101497 -
Journal of Lipid Research Dec 2002Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1) Clinical implications of human LPL gene variations: common... (Review)
Review
Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1) Clinical implications of human LPL gene variations: common mutations and their effects on plasma lipids and coronary heart disease are discussed. 2) LPL actions in the nervous system, liver, and heart: the discussion focuses on LPL and tissue lipid uptake. 3) LPL gene regulation: the LPL promoter and its regulatory elements are described.
Topics: Chylomicrons; Gene Expression Regulation; Genetic Variation; Humans; Lipoprotein Lipase; Liver; Mutation; Myocardium; Nervous System; Organ Specificity
PubMed: 12454259
DOI: 10.1194/jlr.r200015-jlr200 -
Open Biology Apr 2016Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues.... (Review)
Review
Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed-fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8-Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated.
Topics: Angiopoietins; Animals; Biological Transport; Humans; Lipoprotein Lipase; Models, Biological; Signal Transduction; Triglycerides
PubMed: 27053679
DOI: 10.1098/rsob.150272 -
Journal of Lipid Research Sep 2016
Topics: Apolipoproteins; Cardiovascular Physiological Phenomena; Cardiovascular System; Lipoprotein Lipase; Phenotype
PubMed: 27412676
DOI: 10.1194/jlr.C070946 -
FEBS Open Bio Apr 2023The energy demand of breast cancers is in part met through the β-oxidation of exogenous fatty acids. Fatty acids may also be used to aid in cell signaling and toward... (Meta-Analysis)
Meta-Analysis
The energy demand of breast cancers is in part met through the β-oxidation of exogenous fatty acids. Fatty acids may also be used to aid in cell signaling and toward the construction of new membranes for rapidly proliferating tumor cells. A significant quantity of fatty acids comes from the hydrolysis of lipoprotein triacylglycerols and phospholipids by lipoprotein lipase (LPL). The lipid obtained via LPL in the breast tumor microenvironment may thus promote breast tumor growth and development. In this hypothesis article, we introduce LPL, provide a meta-analysis of RNAseq data showing that LPL is associated with poor prognosis, and explain how LPL might play a role in breast cancer prognosis over time.
Topics: Female; Humans; Breast Neoplasms; Fatty Acids; Lipoprotein Lipase; Triglycerides; Tumor Microenvironment
PubMed: 36652113
DOI: 10.1002/2211-5463.13559 -
Journal of Clinical Lipidology 2015In this Roundtable, our intent is to discuss those rare genetic disorders that impair the function of lipoprotein lipase. These cause severe hypertriglyceridemia that... (Review)
Review
In this Roundtable, our intent is to discuss those rare genetic disorders that impair the function of lipoprotein lipase. These cause severe hypertriglyceridemia that appears in early childhood with Mendelian inheritance and usually with full penetrance in a recessive pattern. Dr Ira Goldberg from New York University School of Medicine and Dr Stephen Young from the University of California, Los Angeles have agreed to answer my questions about this topic. Both have done fundamental work in recent years that has markedly altered our views on lipoprotein lipase function. I am going to start by asking them to give us a brief history of this enzyme system as a clinical entity.
Topics: Humans; Hypertriglyceridemia; Lipid Metabolism, Inborn Errors; Lipoprotein Lipase; Portraits as Topic
PubMed: 26073384
DOI: 10.1016/j.jacl.2015.03.009 -
Proceedings of the National Academy of... May 2023The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) is crucial for the delivery of dietary lipids to the heart, skeletal...
The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) is crucial for the delivery of dietary lipids to the heart, skeletal muscle, and adipose tissue. The processing of TRLs by LPL is regulated in a tissue-specific manner by a complex interplay between activators and inhibitors. Angiopoietin-like protein 4 (ANGPTL4) inhibits LPL by reducing its thermal stability and catalyzing the irreversible unfolding of LPL's α/β-hydrolase domain. We previously mapped the ANGPTL4 binding site on LPL and defined the downstream unfolding events resulting in LPL inactivation. The binding of LPL to glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 protects against LPL unfolding. The binding site on LPL for an activating cofactor, apolipoprotein C2 (APOC2), and the mechanisms by which APOC2 activates LPL have been unclear and controversial. Using hydrogen-deuterium exchange/mass spectrometry, we now show that APOC2's C-terminal α-helix binds to regions of LPL surrounding the catalytic pocket. Remarkably, APOC2's binding site on LPL overlaps with that for ANGPTL4, but their effects on LPL conformation are distinct. In contrast to ANGPTL4, APOC2 increases the thermal stability of LPL and protects it from unfolding. Also, the regions of LPL that anchor the lid are stabilized by APOC2 but destabilized by ANGPTL4, providing a plausible explanation for why APOC2 is an activator of LPL, while ANGPTL4 is an inhibitor. Our studies provide fresh insights into the molecular mechanisms by which APOC2 binds and stabilizes LPL-and properties that we suspect are relevant to the conformational gating of LPL's active site.
Topics: Lipoprotein Lipase; Angiopoietin-Like Protein 4; Apolipoprotein C-II; Protein Domains; Catalytic Domain; Triglycerides
PubMed: 37094117
DOI: 10.1073/pnas.2221888120 -
PloS One 2023Lipoprotein lipase (LPL), a crucial enzyme in the intravascular hydrolysis of triglyceride-rich lipoproteins, is a potential drug target for the treatment of...
Lipoprotein lipase (LPL), a crucial enzyme in the intravascular hydrolysis of triglyceride-rich lipoproteins, is a potential drug target for the treatment of hypertriglyceridemia. The activity and stability of LPL are influenced by a complex ligand network. Previous studies performed in dilute solutions suggest that LPL can appear in various oligomeric states. However, it was not known how the physiological environment, that is blood plasma, affects the action of LPL. In the current study, we demonstrate that albumin, the major protein component in blood plasma, has a significant impact on LPL stability, oligomerization, and ligand interactions. The effects induced by albumin could not solely be reproduced by the macromolecular crowding effect. Stabilization, isothermal titration calorimetry, and surface plasmon resonance studies revealed that albumin binds to LPL with affinity sufficient to form a complex in both the interstitial space and the capillaries. Negative stain transmission electron microscopy and raster image correlation spectroscopy showed that albumin, like heparin, induced reversible oligomerization of LPL. However, the albumin induced oligomers were structurally different from heparin-induced filament-like LPL oligomers. An intriguing observation was that no oligomers of either type were formed in the simultaneous presence of albumin and heparin. Our data also suggested that the oligomer formation protected LPL from the inactivation by its physiological regulator angiopoietin-like protein 4. The concentration of LPL and its environment could influence whether LPL follows irreversible inactivation and aggregation or reversible LPL oligomer formation, which might affect interactions with various ligands and drugs. In conclusion, the interplay between albumin and heparin could provide a mechanism for ensuring the dissociation of heparan sulfate-bound LPL oligomers into active LPL upon secretion into the interstitial space.
Topics: Lipoprotein Lipase; Heparin; Ligands; Triglycerides; Hydrolysis; Angiopoietin-Like Protein 4; Albumins
PubMed: 37043509
DOI: 10.1371/journal.pone.0283358