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PubMed1984

Response of adipose tissue lipoprotein lipase activity and serum lipoproteins to acute hyperinsulinaemia in man.

In order to assess the short-term effects of hyperinsulinaemia and hyperglycaemia on adipose tissue lipoprotein lipase activity and on serum lipoproteins, we measured these variables in ten normal subjects during euglycaemic and hyperglycaemic hyperinsulinaemic clamps. The mean steady-state plasma glucose and insulin concentrations, respectively, were 4.7 mmol/l and 101 mU/l during euglycaemic moderate-insulin clamp, 4.9 mmol/l and 565 mU/l during euglycaemic high-insulin clamp, and 8.8 mmol/l and 148 mU/l during hyperglycaemic clamp. Saline infusion was used as control. The adipose tissue lipoprotein lipase activity rose significantly over 5 h during high-insulin clamp (p less than 0.01) and during hyperglycaemic clamp (p less than 0.05), but did not change during the moderate-insulin clamp. The magnitude of change of lipoprotein lipase activity from baseline (either rise or fall) was inversely related to the preclamp activity during euglycaemic moderate-insulin clamp (r = -0.67), during hyperglycaemic clamp (r = -0.68) and during infusion of saline (r = -0.75, p less than 0.05). Total serum triglyceride concentration decreased significantly during all clamp studies compared with the control experiment. This change was mainly accounted for by a decrease of VLDL triglyceride. The LDL cholesterol level fell by an average of 5% (p less than 0.05) during the high-insulin clamp and by 10% (p less than 0.05) during the hyperglycaemic clamp. The HDL cholesterol level did not change significantly. It is concluded that adipose tissue lipoprotein lipase activity in man is increased by physiological insulin levels during hyperglycaemia and also by supraphysiological insulin levels during euglycaemia, but is not influenced by physiological hyperinsulinaemia without hyperglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1982

Alterations in plasma proteins and lipoproteins in acute myocardial infarction: effects on activation of lipoprotein lipase.

Plasma lipoprotein concentrations were followed in 21 men with acute myocardial infarction. HDL and LDL cholesterol concentrations showed similar time-courses with average maximal decreases of about 20%, 10-14 days after onset of symptoms. The decrease in HDL levels (measured as HDL cholesterol and apolipoprotein AI) was significantly correlated to the inflammatory response, as reflected by plasma orosomucoid concentrations, and to the extent of myocardial injury, as mirrored by serum activities of lactate dehydrogenase. In samples drawn 10 days after myocardial infarction we found marked changes in the ability of the patients' sera to enhance the activity of purified lipoprotein lipase. The maximal activating ability (at saturating serum concentrations) increased by about 30%; however, at suboptimal serum concentrations, the activating ability of the patients' sera declined (50% higher serum concentrations were required to reach half maximal reaction rate). The altered activation characteristics were correlated to the changes in HDL concentrations. By affecting the activity of lipoprotein lipase and thereby the rate of intravascular lipoprotein metabolism, this phenomenon may contribute to the lipoprotein alterations seen after myocardial infarction.

Adult↗
PubMedDate not supplied

[Fish proteins moderate triacylglycerols, activities of hepatic triacylglycerol lipase and tissue lipoprotein lipases in hypertensive and diabetic rats].

Fish proteins effect compared with casein was determined on triacylglycerols (TG) metabolism and activities of hepatic triacylglycerol lipase (HTGL) and tissue lipoprotein lipases (LPL), in SHR and diabetic SHR. Two groups of rats (n=24) were fed, 2 months, diet containing 20% casein (CAS) or 20% fish proteins (FP). One month before sacrifice, diabetes was induced in one group of rats by a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg of body weight). FP vs. CAS showed a significant decrease of TG concentrations in plasma (-41%) and liver (-66%), in SHR-STZ. VLDL-LDL mass, which represented the amount of apolipoproteins, TG, phospholipids (PL), unesterified cholesterol (UC), and cholesteryl esters (CE), decreased by 21 and 16% with FP vs. CAS, in SHR and SHR-STZ, respectively, and was concomitant with its low TG. Indeed, TG values was 1.35- and 1.82-fold lower in SHR and SHR-STZ, respectively. In HDL2, a TG diminution of 13% was noted, in SHR with FP vs. CAS. In SHR-STZ with FP, TG and PL were enhanced by 11% and 27%, respectively compared to SHR. HTGL activity decreased by 22% in SHR fed FP compared to those fed CAS. In SHR-STZ with CAS vsSHR, this activity was decreased by 21%. LPL activity in heart was enhanced by 19% in SHR-STZ vs. SHR with FP, when that of muscle was diminished 1.5-fold in SHR with FP vs. CAS and 1.8-fold in SHR-STZ vs. SHR with CAS. Adipose LPL activity was 1.36-fold higher in SHR with FP than CAS. In conclusion, it appears that fish proteins have a hypotriglyceridemic effect, which the mechanism can differ in SHR or SHR-STZ. It may be of interest to propose these fish proteins as lipid metabolism regulator in diseases with hypertriglyceridemia.

Animals↗
PubMed1996

Molecular pathobiology of the human lipoprotein lipase gene.

Lipoprotein lipase (LPL; E.C. 3.1.1.34) is a key enzyme in the metabolism of lipids. Many diseases, including obesity, coronary heart disease, chylomicronemia (pancreatitis), and atherosclerosis, appear to be directly or indirectly related to abnormalities in LPL function. Human LPL is a member of a superfamily of lipases that includes hepatic lipase and pancreatic lipase. These lipases are characterized by extensive homology, both at the level of the gene and the mature protein, suggesting that they have a common evolutionary origin. A large number of natural mutations have been discovered in the human LPL gene, which are located at different sites in the gene and affect different functions of the mature protein. There is a high prevalence of two of these mutations (207 and 188) in the Province of Québec, and one of them (207) is almost exclusive to the French-Canadian population. A study of these and other naturally occurring mutant LPL molecules, as well as those created in vitro by site-directed mutagenesis, indicate that the sequence of LPL is organized into multiple structural and functional units that act in concert in the normal enzyme. In this review, we discuss the interrelationships of LPL structure and its function, the molecular etiology of abnormal LPL in humans, and the clinical and therapeutic aspects of LPL deficiency.

Amino Acid Sequence↗
PubMed1990

Frameshift mutation in exon 3 of the lipoprotein lipase gene causes a premature stop codon and lipoprotein lipase deficiency.

Several mutations in the human lipoprotein lipase (LPL) gene have been shown to underlie LPL deficiency. These mutations occur in patients who are mainly of European descent, and comprise a single base transition causing a premature stop codon, four separate amino acid substitutions and two large gene rearrangements. Together they account for approximately 40% of the LPL alleles in a cohort of 50 patients whose DNA has been examined in this laboratory. We now report on a new mutation in exon 3 of the LPL gene from a South African subject of South-east Asian extraction. This mutation comprises a six base-pair insertion at the site of a single base deletion. The net insertion of five base-pairs at amino acid positions 102 to 103 causes a shift in the reading frame, generating 44 amino acid residues of random sequence and a premature stop codon within exon 4. This mutation is predicted to result in the synthesis of a markedly truncated protein and is the cause of the enzyme deficiency in our patient.

Adult↗
PubMed1998

Lipoprotein lipase transport in plasma: role of muscle and adipose tissues in regulation of plasma lipoprotein lipase concentrations.

Lipoprotein lipase (LPL) is synthesized in tissues involved in fatty acid metabolism such as muscle and adipose tissue. LPL is also found in the circulation, but is mostly lipolytically inactive. The proportion of active circulating LPL increases after a fatty meal. We investigated the release of active and inactive LPL from adipose tissue and muscle in the fasting and postprandial states. Arteriovenous concentration gradients of LPL across adipose tissue and forearm muscle were measured in male subjects before and after a fat-rich meal (n = 7) and before and during infusion of a triacylglycerol emulsion (Intralipid) (n = 6). Plasma LPL activity rose after the meal and more so during Intralipid infusion. Plasma LPL mass (>95% inactive LPL) increased after the meal but decreased after Intralipid infusion. In the fasting state (n = 13) muscle efflux of LPL activity was 0.263 +/- 0.098 mU/min per 100 ml of muscle tissue whereas there was an influx of LPL activity to adipose tissue of 0.085 +/- 0.100 mU/min per 100 g of adipose tissue (P < 0. 02 muscle vs. adipose tissue). Similarly in the postprandial state only muscle released LPL activity. Both tissues released LPL mass. In the fasting state efflux was 17.8 +/- 8.8 ng/min per 100 ml muscle and 55.2 +/- 21.3 ng/min per 100 g of adipose tissue (P < 0. 05 muscle vs. adipose tissue). Release of LPL, either active or inactive, was not correlated with levels of non-esterified fatty acids or plasma triacylglycerol. In conclusion, there is a substantial release of LPL from adipose tissue and muscle, most of which is inactive. A small proportion of active LPL seems to be redistributed from muscle to adipose tissue.

Adipose Tissue↗
PubMed1983

Familial lipoprotein lipase and apolipoprotein C-II deficiency. Lipoprotein and apoprotein analysis, adipose tissue and hepatic lipoprotein lipase levels in seven patients and their first degree relatives.

Plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic lipase (H-TGL) were studied in 7 patients with familial hyperchylomicronemia from four different families. Their first-degree relative were also studied. The patients were heterogeneous for the genetic defect; LPL activity was absent in five patients (LPL deficiency) but normal in two. However, these two did not have apo C-II, the physiological activator of LPL (C-II deficiency). There were no significant differences in the clinical picture between patients with LPL deficiency and C-II deficiency. In both mutants, marked hypertriglyceridemia was due to an accumulation of lipoproteins of density less than 1.006 g/ml. The LDL fraction was very reduced and abnormal in composition, presenting a CH/TG ratio of 0.5. The plasma apolipoprotein B (apo B) level was low (67 +/- 5.5 mg/dl) and was transported mainly in the VLDL fraction (26 +/- 3.2 mg/dl) rather than in the LDL fraction (15 +/- 1.4 mg/dl). Very low levels of cholesterol and apolipoprotein A-I in HDL subfractions HDL2 and HDL3 were also recorded. Only 3 out of the 24 first-degree relatives of patients with LPL deficiency showed even a small increase in plasma triglycerides, but 15 had low or low to normal LPL values. H-TGL levels were normal in all subjects. The 4 first-degree relatives of C-II deficiency patients showed normal levels of plasma lipids. LPL and H-TGL, and 2 children of 1 patient showed normal distribution of apo C peptides in their VLDL. A block in chylomicron catabolism, due to the absence of LPL or apo C-II, may lead to a massive accumulation of lipoproteins with a density less than 1.006 g/ml, and a drastic reduction in the LDL and HDL fractions. Low LPL values in the first-degree relatives of LPL deficiency patients might represent a biochemical marker for healthy carriers of LPL deficiency.

Adipose Tissue↗
PubMed1989

Genetic and developmental regulation of the lipoprotein lipase gene: loci both distal and proximal to the lipoprotein lipase structural gene control enzyme expression.

We report here a study of the developmental and genetic control of tissue-specific expression of lipoprotein lipase, the enzyme responsible for hydrolysis of triglycerides in chylomicrons and very low density lipoproteins. Lipoprotein lipase (LPL) mRNA is present in a wide variety of adult rat and mouse tissues examined, albeit at very different levels. A remarkable increase in the levels of LPL mRNA occurs in heart over a period of several weeks following birth, closely paralleling developmental changes in lipase activity and myocardial beta-oxidation capacity. Large increases in LPL mRNA also occur during differentiation of 3T3L1 cells to adipocytes. As previously reported, at least two separate genetic loci control the tissue-specific expression of LPL activity in mice. One of the loci, controlling LPL activity in heart, is associated with an alteration in LPL mRNA size, while the other, controlling LPL activity in adipose tissue, appears to affect the translation or post-translational expression of LPL. To examine whether these genetic variations are due to mutations of the LPL structural locus, we mapped the LPL gene to a region of mouse chromosome 8 using restriction fragment-length polymorphisms and analysis of hamster-mouse somatic cell hybrids. This region is homologous to the region of human chromosome 8 which contains the human LPL gene as judged by the conservation of linked genetic markers. Genetic variations affecting LPL expression in heart cosegregated with the LPL gene, while variations affecting LPL expression in adipose tissue did not. 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. These results suggest the existence of cis-acting elements for LPL gene expression that operate in heart but not adipose tissue. Our results also indicate that two genetic mutations resulting in deficiencies of LPL in mice, the W mutation on chromosome 5 and the cld mutation on mouse chromosome 17, do not involve the LPL structural gene locus. Finally, we show that the gene for hepatic lipase, a member of a gene family with LPL, is unlinked to the gene for LPL. This indicates that combined deficiencies of LPL and hepatic lipase, observed in humans as well as in certain mutant strains of mice, do not result from focal disruptions of a cluster of lipase genes.

Adipose Tissue↗
PubMed1989

Adrenergic blocking agents and lipoprotein lipase activity.

Lipoprotein lipase activity, total serum cholesterol and triglycerides, HDL cholesterol were determined before and after two weeks of treatment with a low dose of an alpha 1-blocking agent (prazosin) or of a beta-adrenergic-blocking drug (metoprolol). Lipoprotein lipase activity was almost doubled after prazosin (p less than 0.02) and practically unchanged after metoprolol, at a time and at a drug dosage when only minor changes in blood pressure and serum lipids were detectable. HDL cholesterol was slightly but significantly increased after prazosin (p less than 0.05). Heart rate was increased after prazosin (p less than 0.05) and decreased after metoprolol (p less than 0.01).

Adult↗
PubMed1998

Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: direct evidence that lipoprotein lipase bridging occurs in vivo.

Lipoprotein lipase (LPL) is the central enzyme in plasma triglyceride hydrolysis. In vitro studies have shown that LPL also can enhance lipoprotein uptake into cells via pathways that are independent of catalytic activity but require LPL as a molecular bridge between lipoproteins and proteoglycans or receptors. To investigate whether this bridging function occurs in vivo, two transgenic mouse lines were established expressing a muscle creatine kinase promoter-driven human LPL (hLPL) minigene mutated in the catalytic triad (Asp156 to Asn). Mutated hLPL was expressed only in muscle and led to 3,100 and 3,500 ng/ml homodimeric hLPL protein in post-heparin plasma but no hLPL catalytic activity. Less than 5 ng/ml hLPL was found in preheparin plasma, indicating that proteoglycan binding of mutated LPL was not impaired. Expression of inactive LPL did not rescue LPL knock-out mice from neonatal death. On the wild-type (LPL2) background, inactive LPL decreased very low density lipoprotein (VLDL)-triglycerides. On the heterozygote LPL knock-out background (LPL1) background, plasma triglyceride levels were lowered 22 and 33% in the two transgenic lines. After injection of radiolabeled VLDL, increased muscle uptake was observed for triglyceride-derived fatty acids (LPL2, 1.7x; LPL1, 1.8x), core cholesteryl ether (LPL2, 2.3x; LPL1, 2.7x), and apolipoprotein (LPL1, 1.8x; significantly less than cholesteryl ether). Skeletal muscle from transgenic lines had a mitochondriopathy with glycogen accumulation similar to mice expressing active hLPL in muscle. In conclusion, it appears that inactive LPL can act in vivo to mediate VLDL removal from plasma and uptake into tissues in which it is expressed.

Animals↗
PubMed1996

Compound heterozygosity for a known and a novel defect in the lipoprotein lipase gene (Asp250-->Asn; Ser251-->Cys) resulting in lipoprotein lipase (LPL) deficiency.

Two missense mutations in exon 6 of the LPL gene were identified on separate alleles in a Dutch patient with lipoprotein lipase (LPL) deficiency. The first mutation is a G1003-->A transition resulting in a D250N mutation, which has been shown previously to result in a catalytically defective protein in patients of French-Canadian ancestry. The second mutation, a C to G transition at nucleotide 1007, predicts a S251C residue change in the highly conserved region of LPL surrounding the loop structure the covers the catalytic triad. This mutation constitutes a novel defect among LPL gene mutations reported so far. Site-directed mutagenesis experiments provide in-vitro evidence for the complete loss of LPL activity resulting from this latter missense mutation. The G1003-->A nucleotide substitution underlying the Asp250 mutation deletes a TaqI endonuclease recognition site and the C1007-->G change that leads to the S251C alteration abolishes a HinfI recognition site. This will facilitate rapid screening for these mutations in LPL-deficient patients.

Adolescent↗
PubMed2004

Pre-heparin lipoprotein lipase mass.

Lipoprotein lipase (LPL) is a lipolytic enzyme involved in catalyzing the hydrolysis of triglycerides (TG) in chylomicrons and very low-density lipoprotein (VLDL) particles. Over the last decade, the clinical significance of measuring LPL mass without heparin injection has been increasingly studied. In earlier studies, it was shown that this marker was utilized to classify type 1 hyperlipoproteinemia, which is an extremely rare metabolic disorder. Later, researchers paid more attention to the clinical significance of measuring this parameter in more common metabolic disorders. Studies have shown that pre-heparin plasma LPL mass has significant relationships with serum lipid and lipoproteins, visceral fat area, and even a marker for acute inflammation, although this might be a metabolic surrogate marker which does not appear to be involved in catalyzing the hydrolysis of TG in TG-rich lipoproteins. We suggest that pre-heparin LPL mass in plasma or sera provides us with useful and important information on the pathophysiology of metabolic disorders or acute inflammation despite its simplicity from a practical point of view.

Adipose Tissue↗
PubMed1988

Familial lipoprotein lipase deficiency: abnormal lipoproteins and defective metabolism of low density lipoproteins in cultured human skin fibroblasts.

Lipoproteins (chylomicrons + VLDL, VLDL, IDL, LDL and HDL) were separated from the plasma of 2 patients with primary, familial lipoprotein lipase deficiency. Chylomicrons were excessively enriched with cholesteryl esters. VLDL and IDL were of almost normal composition. LDL separated into 2 fractions LDL1 and LDL2, both triglyceride- and protein-rich and cholesteryl ester-poor. LDL2, the main LDL fraction, was denser and smaller than normal LDL. HDL3 was the only HDL population identified and was also triglyceride- and protein-rich and cholesteryl ester-poor. These observations indicate excessive triglyceride and cholesteryl ester transfer between chylomicrons and LDL and HDL. VLDL and its immediate catabolic product, IDL, seem to be spared the effects of the lipid transfer reaction. The biological reactivity of LDL1 and LDL2 was investigated in upregulated cultured human skin fibroblasts. Both exhibited defective specific binding to the LDL receptor and ineffective capacity to down-regulate sterol synthesis. These abnormalities were more pronounced with LDL3. The ineffective downregulation of sterol synthesis is most probably due to both the cholesterol content of the LDLs and their reduced binding to the LDL receptor. The defective binding of the LDLs to the receptor can be attributed to the abnormal composition of the lipoproteins and, to a lesser degree, reduced diameters (only LDL2). It is concluded that abnormal composition of LDL, in particular of lipid moieties, may change the affinity of the moiety of the lipoprotein towards the LDL receptor.

Adult↗
PubMed2000

The translational regulation of lipoprotein lipase in diabetic rats involves the 3'-untranslated region of the lipoprotein lipase mRNA.

Adipose tissue lipoprotein lipase (LPL) activity is decreased in patients with poorly controlled diabetes, and this contributes to the dyslipidemia of diabetes. To study the mechanism of this decrease in LPL, we studied adipose tissue LPL expression in male rats with streptozotocin-induced diabetes. Heparin releasable and extractable LPL activity in the epididymal fat decreased by 75-80% in the diabetic group and treatment of the rats with insulin prior to sacrifice reversed this effect. Northern blot analysis indicated no corresponding change in LPL mRNA levels. However, LPL synthetic rate, measured using [(35)S]methionine pulse labeling, was decreased by 75% in the diabetic adipocytes, and insulin treatment reversed this effect. These results suggested regulation of LPL at the level of translation. Diabetic adipocytes demonstrated no change in the distribution of LPL mRNA associated with polysomes, suggesting no inhibition of translation initiation. Addition of cytoplasmic extracts from control and diabetic adipocytes to a reticulocyte lysate system demonstrated the inhibition of LPL translation in vitro. Using different LPL mRNA transcripts in this in vitro translation assay, we found that the 3'-untranslated region (UTR) of the LPL mRNA was important in controlling translation inhibition by the cytoplasmic extracts. To identify the specific region involved, gel shift analysis was performed. A specific shift in mobility was observed when diabetic cytoplasmic extract was added to a transcript containing nucleotides 1818-2000 of the LPL 3'-UTR. Thus, inhibition of translation is the predominant mechanism for the decreased adipose tissue LPL in this insulin-deficient model of diabetes. Translation inhibition involves the interaction of a cytoplasmic factor, probably an RNA-binding protein, with specific sequences of the LPL 3'-UTR.

3' Untranslated Regions↗
PubMed1986

Inhibition of human and rat lipoprotein lipase by high-density lipoprotein.

The hydrolysis in vitro of preactivated Intralipid (an artificial triacylglycerol-phospholipid emulsion) by rat adipose tissue lipoprotein lipase is inhibited by rat high-density lipoprotein (HDL). The aim of this work was to investigate whether human lipoprotein lipase was also inhibited, the mechanism of inhibition of the rat enzyme by HDL, and the role of the various individual apolipoproteins. Both human and rat lipoprotein lipase from post-heparin plasma are inhibited by HDL. This inhibition is considerably decreased if the HDL is first made 'apolipoprotein poor' by removal of some transferable apolipoproteins. In contrast, both native and apolipoprotein poor HDL inhibit the hydrolysis of Intralipid by rat hepatic lipase. Apolipoproteins C and E, either free in solution or attached to lipid vesicles, inhibit the hydrolysis of activated Intralipid by rat lipoprotein lipase to a maximum of 85% and 50%, respectively. Apolipoprotein A attached to vesicles gives little inhibition. HDL apolipoprotein and apolipoprotein C compete with the substrate for binding to lipoprotein lipase with apolipoprotein C having a higher affinity for the enzyme than HDL apolipoprotein. The inhibition of lipoprotein lipase by HDL can be explained by the association of the constituent apolipoproteins, in particular apolipoprotein C, with the enzyme so that there is less enzyme available to act on substrate.

Animals↗
PubMed1981

Specificity of lipoprotein lipase and hepatic lipase toward monoacylglycerols varying in the acyl composition.

We report here that both the hepatic lipase and lipoprotein lipase demonstrate specificity towards the acyl group present on monoacylglycerols. We found that unsaturated glycerides are more readily degraded than saturated glycerides. However, the basis for this specificity appears to be different for each enzyme. The activity of the hepatic lipase, but not the lipoprotein lipase, could be stimulated by Triton X-100 and phosphoglycerides. We interpret these results to show that while both the lipoprotein lipase and hepatic lipase are sensitive to the physical state of the substrate (as shown by fluorescence depolarization), the lipoprotein lipase also has a low affinity for monoacylglycerols that contain a saturated acyl group. In the course of this study we also obtained evidence that some type of phase separation occurs when mixtures of saturated and unsaturated monoacylglycerols are prepared.

Animals↗