Disease relevance of Lpl

• Increased LPL activity completely normalized hypertriglyceridemia of apoa5-deficient mice; however, overexpression of human apoAV modulated triglyceride levels only slightly when LPL was reduced [1].
• Taken together, these data indicate that macrophage LPL expression in the artery wall promotes atherogenesis during foam cell lesion formation, but this impact may be limited to macrophage-rich lesions [2].
• Although both groups developed hypercholesterolemia to a comparable degree in response to an atherogenic diet, the LPL/APOEKO mice developed 2-fold smaller fatty streak lesions in the aortic sinus compared to the APOEKO mice [3].
• After eating an atherogenic diet, LPL+/- as compared to LPL+/+ mice have more dyslipidemia, but no more atherosclerosis, and less LPL protein in atherosclerotic lesions [4].
• Remarkably, after focal cerebral ischemia, the expression of EL was unaffected whereas a dramatic increase in LPL expression was observed in neocortical areas of the lesioned side of the brain [5].

High impact information on Lpl

• Chylomicrons formed in the intestinal mucosa during the absorption of the products of digestion, are processed by the peripheral circulation by lipoprotein lipase, which catalyses the breakdown of triglycerides in chylomicrons to free fatty acids and glycerol [6].
• We have found previously that macrophages secrete the hormone cachectin, which specifically suppresses LPL activity in cultured adipocytes (3T3-L1 cells) [7].
• Among these changes, a hypertriglyceridaemic state is frequently evident, resulting from defective triglyceride clearance, caused by systemic suppression of the enzyme lipoprotein lipase (LPL) [7].
• A single recessive mutation, cld, on mouse chromosome 17 causes an apparent deficiency of both lipoprotein lipase and hepatic triglyceride lipase activities [8].
• The factor(s) secreted by fully activated macrophages that inhibited LPL secretion was shown to be thermolabile and distinct from tumor necrosis factor [9].

Chemical compound and disease context of Lpl

• Lipoprotein lipase and endothelial lipase expression in mouse brain: regional distribution and selective induction following kainic acid-induced lesion and focal cerebral ischemia [5].
• This would suggest that hypertriglyceridemia and hypercholesterolemia result from inhibition of LPL and C7alphaH, respectively, while the biologic activity of CETP and LCAT are indirectly increased to compensate for the increased cholesterol burden [10].
• It is known to bind a wide variety of unrelated ligands including alpha 2-macroglobulin-proteinase complexes, tissue plasminogen activator, apolipoprotein E-enriched very low density lipoprotein, lipoprotein lipase, and Pseudomonas exotoxin A [11].
• Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets [12].
• Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein by a lipoprotein lipase (LPL)-dependent pathway [13].

Biological context of Lpl

• Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins [14].
• These results suggest the existence of cis-acting elements for LPL gene expression that operate in heart but not adipose tissue [15].
• It is proposed, that apoAV reduces triglyceride levels by guiding VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis [1].
• Lipoprotein lipase (LPL) is an important enzyme in adipocyte and lipid metabolism with complex cellular regulation [16].
• The functional interplay between apoAV and LPL was further investigated by cross-breeding a human LPL transgene with the apoa5 knock-out and the hAPOA5tr to an lpl-deficient background [1].

Anatomical context of Lpl

• In contrast, mouse AT and isolated adipocytes that lacked LPL expressed large amounts of EL mRNA [17].
• Endothelial lipase provides an alternative pathway for FFA uptake in lipoprotein lipase-deficient mouse adipose tissue [17].
• After 19 weeks of diet, the lesions in the proximal aorta were complex with relatively few macrophages expressing LPL protein and mRNA in LPL(+/+) --> LDLR(-/-) mice [2].
• Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT [18].
• Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle [18].

Associations of Lpl with chemical compounds

• On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 versus 236 mg/dl) and modest decrease in mean cholesterol levels (300 versus 386 mg/dl) as compared with LDLRKO mice [14].
• Hearts from 3-month-old mice expressing GPI-anchored human LpL (hLpLGPI) mice had increased fatty acid oxidation and heart failure genes and decreased glucose transporter genes [19].
• More luminal, lipid-laden macrophages generally did not stain for LPL, but deeper, lipid-poor macrophages as well as necrotic core regions contained immunoreactive LPL [4].
• Immunofluorescent LPL was not found in normal newborn liver cells unless the cells were treated with monensin, thus demonstrating that normal liver cells synthesized and secreted LPL [20].
• Upregulation of LDLR by lipoprotein-deficient serum/lovastatin in wild-type cells resulted in a 7-fold increase of LPL-mediated LDL uptake [21].

Physical interactions of Lpl

• Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase [1].
• We also found that LPL caused the nuclear migration of one member of the NFkB family that appears to bind to a site in the murine TNF alpha gene promoter [22].
• Hence, we searched for IFNgamma sensitive binding sites within the murine LPL promoter [23].
• In the present study we investigated the effect of the isoform and the amount of apoE per particle, as well as the role of LPL on the binding of beta-VLDL to HSPG [24].

Regulatory relationships of Lpl

• Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice [2].
• Treatment of macrophages with lipoprotein lipase induced tumor necrosis factor alpha gene expression and protein secretion [22].
• In summary, we have identified a STAT 1 binding site within the murine LPL promoter which likely plays a role in the IFNgamma induced decrease of LPL expression [23].
• Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity [25].
• ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis [26].

Other interactions of Lpl

• Thus, the cld mutation appears not to globally disrupt the secretion of all N-linked glycoproteins, but rather selectively impairs LPL and HL at points essential to their normal intracellular transport and secretion [27].
• Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle [18].
• Induction of tumor necrosis factor alpha gene expression by lipoprotein lipase [22].
• Therefore, we performed in situ hybridization for LPL mRNA in tissues from normal and cld pups and adult mice using an antisense 35S-labeled cRNA probe [28].
• Apolipoprotein E, lipoprotein lipase and alpha-2-macroglobulin messenger RNA levels in total embryos increased progressively, beginning most pronounced at days 13, 15 and 17, respectively [29].
• Also, an injection of Intralipid released LPL into the plasma of wild-type mice but was ineffective in releasing LPL in Gpihbp1(-/-) mice [30].

Analytical, diagnostic and therapeutic context of Lpl

• Furthermore, Southern blotting analysis indicates that LPL is encoded by a single gene and, thus, the genetic differences are not a consequence of independent regulation of two separate genes in the two tissues [15].
• Plasma levels of CETP, lipoprotein lipase, and hepatic lipase were not changed by castration [31].
• Heterozygous lipoprotein lipase deficiency (LPL+/-) is common and has been implicated in premature atherosclerosis in epidemiologic studies [4].
• Immunofluorescence studies showed that LPL is retained in endoplasmic reticulum (ER) in cld/cld cells [32].
• Electrophoretic mobility shift assays using two 32P-labeled LPL probes spanning the region between -180 and +44 bp revealed the loss of several LPL DNA-protein interactions after TNF alpha treatment, including the binding of NF-Y to the CCAAT box and a protein to the octamer consensus sequence [33].

References