Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewPhysiological regulation of lipoprotein lipase
Introduction
Many tissues rely on plasma triglycerides (TG) as an important source of fatty acids for subsequent oxidation and/or storage. Plasma TG are packaged into the TG-rich lipoproteins chylomicrons and very low-density lipoproteins (VLDL), which carry TG coming from the diet or synthesized in the liver, respectively. Utilization of plasma TG is dependent on lipoprotein lipase (LPL), which is attached to the capillary endothelium and catalyzes the hydrolytic cleavage of TG into fatty acids. LPL, originally referred to as clearing factor lipase [1], is produced by a limited number of cells that include (cardio)myocytes and adipocytes, and upon release by these cells is transported to the lumenal side of the capillary endothelium by the protein GPIHBP1 [2], [3]. The luminal or endothelial LPL is referred to as the functional LPL pool, as it represents the portion of tissue LPL that is actively involved in plasma TG hydrolysis. Additionally, LPL is produced by macrophages and mammary gland secretory cells, and by fetal hepatocytes. Maturation of nascent LPL occurs in the endoplasmic reticulum and is promoted by the lipase maturation factor 1 [4]. The LPL enzyme is catalytically active as a dimer composed of two glycosylated 55 kDa subunits connected in a head-to-tail fashion by non-covalent interactions [5], [6].
The human LPL gene consists of 9 exons and encodes a protein of 475 amino acids that can be divided into distinct structural and functional domains, including an N-terminal signal sequence, a catalytic domain, a ‘lid’ domain that covers the active site, and a C-terminal domain [7], [8]. The catalytic triad for the active site is formed by the amino acids Ser159, Asp183, and His266. Recent evidence indicates that the C-terminal portion of LPL, which mediates binding to heparin, is sufficient for binding to GPIHBP1 [9], [10]. Accordingly, formation of the full length LPL homodimers is not required for interactions with GPIHBP1. Finally, LPL is subject to proteolytic cleavage by proprotein convertases at residue 297, which represents a potential regulatory mechanism [11].
The essential role of LPL in plasma TG clearance is illustrated by the severe hypertriglyceridemia in patients carrying mutations within the LPL gene [12]. Similarly, mice with a generalized deletion of LPL have markedly higher plasma TG levels at birth and die within 24 h due to an inability to process the milk lipids. At the time of death, LPL knockout (KO) pups are severely hypertriglyceridemic [13], [14]. Tissue-specific deletions of LPL have further demonstrated the importance of LPL for local fatty acid uptake [15], [16], [17]. Deletion or disabling mutations in the GPIHBP1 gene also give rise to marked hypertriglyceridemia in mice and humans [3], [18]. Conversely, transgenic mice overexpressing human LPL throughout the body show a 75% reduction in plasma TG [19].
Because LPL is a critical determinant of plasma TG clearance and resultant tissue uptake of fatty acids, the activity of LPL needs to be carefully regulated in order to match the rate of uptake of plasma TG-derived fatty acids to the needs of the underlying tissue and the ability of the tissue to dispose of the fatty acids, all while being confronted with huge fluctuations in the production of TG-rich lipoproteins. It will therefore come as no surprise that the activity of LPL is extensively regulated through multiple mechanisms, which primarily operate at the transcriptional and post-translational level. Regulation of DNA transcription is responsible for the upregulation of LPL gene expression and activity during (cardio)myogenesis and adipogenesis [20], [21], [22]. However, most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. This review will summarize the current literature on regulation of LPL activity in various tissues, focusing on LPL regulation in response to physiological stimuli.
Section snippets
Two groups of LPL modulating proteins
As indicated above, physiological variation in LPL activity in various tissues is primarily achieved via post-translational mechanisms involving a number of extracellular proteins. These proteins can be divided into two main groups. The first group encompasses the apolipoproteins APOC1, APOC2, APOC3, APOA5, and APOE, which are mainly or exclusively produced in liver and are physically associated with a variety of lipoprotein particles including TG-rich lipoproteins. The second group includes
Lipid sources for adipocytes
Adipocytes can acquire fatty acids for storage from three principal sources. The first source is de novo lipogenesis in adipocytes from glucose and acetate. The importance of this pathway is highly dependent on the animal species, and appears to be relatively insignificant in humans [87], [88]. The second source is circulating FFA. Since circulating FFA mostly originate from adipose tissue, uptake of plasma FFA by adipose tissue essentially represents recycling of stored fatty acids and
Lipid sources for myocytes
Myocytes acquire fatty acids from plasma FFA and circulating TG-rich lipoproteins [90]. The absolute and relative importance of each of these two sources is influenced by a variety of factors, with nutritional status and physical exercise being the dominant ones. In addition, fuel use is determined by fiber type [161]. Type 1 oxidative slow-twitch fibers are heavily reliant on lipid fuels, whereas Type IIB glycolytic fast twitch fibers prefer glucose and glycogen. When fatty acid uptake exceeds
Lipid sources for heart
Cardiac contractility depends on the adequate delivery of oxygen and energy substrates to the heart followed by oxidation of energy substrates to yield ATP. The energy requirements of the contracting heart are mainly met by fatty acid oxidation, with the remainder of energy coming from oxidation of glucose and lactate [189], [190]. Although fatty acids are thus essential for cardiac contractility, excessive uptake of fatty acids causes lipid overload or lipotoxicity and may disturb cardiac
Lipid sources for brown adipocytes
The physiological function of brown adipose tissue is to generate heat and maintain body temperature as part of cold-adaptive thermogenesis [206]. In many animal species, cold provokes chronic expansion of BAT mass as well as changes in BAT morphology and specific enzymatic activity, together leading to a marked increase in total thermogenic capacity. Recent studies in human subjects indicate cold-induced hypermetabolic activity in multifocal regions along the neck, supraclavicular regions,
Role of lipoprotein lipase in macrophages
It has long been recognized that macrophages have the ability to hydrolyze TG within chylomicrons via lipase activity and oxidize or re-esterify the released fatty acids [232], [233], [234], [235]. The TG-depleted and cholesterol-enriched remnant is subsequently taken up by macrophages via an APOE-mediated process [236]. Most of the published studies on LPL in macrophages have addressed the potential impact of LPL on foam cell formation and atherogenesis, showing expression of LPL in
LPL activity in the lung
In addition to its well established expression and function in adipose tissue, muscle, and macrophages, LPL enzyme activity has been detected in other tissues and cells, including lung, lactating mammary gland, brain, and kidney. Expression of LPL in lung is related to the abundance of LPL-expressing macrophages [279]. It has been proposed that LPL activity in lung cancer tissue predicts shorter survival in patients with non-small cell lung cancer [280]. Based on its macrophage origin, it can
Conclusion
The cellular uptake of fatty acids needs to be adjusted to local requirements and thus highly fluctuates between different tissues and between different physiological and nutritional states. By catalyzing the hydrolysis of circulating TG, LPL serves as one of the central gatekeepers that controls local fatty acid uptake. Consistent with this important function, the activity of LPL is subject to multiple regulatory mechanisms via a number of regulatory proteins. Some of these mechanisms are
References (299)
Clearing factor, a heparin-activated lipoprotein lipase. I. Isolation and characterization of the enzyme from normal rat heart
J. Biol. Chem.
(1955)- et al.
GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries
Cell Metab.
(2010) - et al.
Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons
Cell Metab.
(2007) - et al.
Lipoprotein lipase from bovine milk. Isolation procedure, chemical characterization, and molecular weight analysis
J. Biol. Chem.
(1976) - et al.
Comparative studies of vertebrate lipoprotein lipase: a key enzyme of very low density lipoprotein metabolism
Comp. Biochem. Physiol. Part D Genomics Proteomics
(2011) - et al.
Lipoprotein lipase. Molecular model based on the pancreatic lipase X-ray structure: consequences for heparin binding and catalysis
J. Biol. Chem.
(1994) - et al.
Identification of a heparin-binding domain in the distal carboxyl-terminal region of lipoprotein lipase by site-directed mutagenesis
J. Lipid Res.
(1998) - et al.
Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases
J. Biol. Chem.
(2010) - et al.
COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity
J. Biol. Chem.
(1995) - et al.
Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression
J. Biol. Chem.
(2004)
Overexpression of human lipoprotein lipase in transgenic mice. Resistance to diet-induced hypertriglyceridemia and hypercholesterolemia
J. Biol. Chem.
Development of lipoprotein lipase in cultured 3T3-L1 cells
Biochem. Biophys. Res. Commun.
Transcriptional regulation of lipoprotein lipase in the heart during development in the rat
Biochem. Biophys. Res. Commun.
A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease
Metabolism
Further characterization of the metabolic properties of triglyceride-rich lipoproteins from human and mouse apoC-III transgenic mice
J. Lipid Res.
Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL
J. Lipid Res.
Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice
J. Lipid Res.
Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL
J. Lipid Res.
Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets
J. Biol. Chem.
Apolipoprotein A-V; a potent triglyceride reducer
Atherosclerosis
Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant
Atherosclerosis
Glucose regulates the expression of the apolipoprotein A5 gene
J. Mol. Biol.
The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element
J. Biol. Chem.
Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators
J. Biol. Chem.
Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice
Biochim. Biophys. Acta
Hepatic uptake of chylomicron remnants
J. Lipid Res.
Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo
J. Biol. Chem.
ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression
J. Lipid Res.
Apolipoprotein E participates in the regulation of very low density lipoprotein-triglyceride secretion by the liver
J. Biol. Chem.
Inhibition of lipoprotein lipase by the receptor-binding domain of apolipoprotein E
FEBS Lett.
Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene
J. Biol. Chem.
Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages
Cell Metab.
The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity
J. Biol. Chem.
Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation
J. Biol. Chem.
Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration
Am. J. Pathol.
ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase
J. Biol. Chem.
The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms
J. Biol. Chem.
GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4
J. Lipid Res.
ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states
Biochem. Biophys. Res. Commun.
Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor
Biochem. Biophys. Res. Commun.
Regulation of the angiopoietin-like protein 3 gene by LXR
J. Lipid Res.
Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels
Biochem. Biophys. Res. Commun.
Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family
Biochem. Biophys. Res. Commun.
Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling
J. Lipid Res.
Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization
Adv. Enzym. Regul.
J. Lipid Res.
Tissue-specific regulation of guinea pig lipoprotein lipase; effects of nutritional state and of tumor necrosis factor on mRNA levels in adipose tissue, heart and liver
Gene
Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism
J. Biol. Chem.
Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia
Nat. Genet.
Molecular modeling of the dimeric structure of human lipoprotein lipase and functional studies of the carboxyl-terminal domain
Eur. J. Biochem.
Cited by (399)
Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease
2024, Bioorganic ChemistryClassic metabolic actions of insulin in humans: from physiology to disease and novel pharmacotherapeutics
2024, Insulin: Deficiency, Excess and Resistance in Human DiseaseA unified model for regulating lipoprotein lipase activity
2024, Trends in Endocrinology and MetabolismAerobic exercise-induced decrease of chemerin improved glucose and lipid metabolism and fatty liver of diabetes mice through key metabolism enzymes and proteins
2023, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsAngiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases
2023, Canadian Journal of CardiologyPotential health risk analysis of chlorantraniliprole in vivo
2023, Science Bulletin