Mechanism of action of lipoprotein lipase

McLean, Larry R.; Demel, R.A.; Socorro, Lilian; Masaki, Shinomiya; Jackson, Richard L.

doi:10.1016/0076-6879(86)29102-8

Cited by 33 publications

(12 citation statements)

References 65 publications

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“…Carboxylesterase (EC 3.1.1.1) enzyme activity was determined spectrophotometrically with pnitrophenyl acetate as substrate according to the method of McLean et al (17). Deglycosylation with endoglycosidase H was performed as described by Harano et al (18).…”

Section: Methodsmentioning

confidence: 99%

Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase.

Satoh

Martin

Schulick

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

126

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Previous studies have demonstrated that patients with halothane-induced hepatitis have serum antibodies that are directed against novel liver microsomal neoantigens and have suggested that these neoantigens may play an immunopathological role in development of the patients' liver damage. These investigations have further revealed that the antibodies are directed against distinct polypeptide fractions (100 kDa, 76 kDa, 59 kDa, 57 kDa, 54 kDa) that have been covalently modified by the reactive trifluoroacetyl halide metabolite of halothane. In this paper, the trifluoroacetylated (TFA) 59-kDa neoantigen (59-kDa-TFA) recognized by the patients' antibodies was isolated from liver microsomes of halothane-treated rats by chromatography on an immunoaffinity column of anti-TFA IgG. Antibodies were raised against the 59-kDa-TFA protein and were used to purify the native protein from liver microsomes ofuntreated rats. Based upon its apparent monomeric molecular mass, NH2-terminal amino acid sequence, catalytic activity, and other physical properties, the protein has been identified as a previously characterized microsomal carboxylesterase (EC 3.1.1.1). A similar strategy may be used to purify and characterize neoantigens associated with other drug toxicities that are believed to have an immunopathological basis.It has been estimated that between 3% and 25% of all drug toxicities, which can include anaphylaxis, serum sickness, asthma, urticaria, dermatitis, fever, hemolytic anemia, thrombocytopenia, granulocytopenia, hepatitis, nephritis, vasculitis, pneumonitis, and lupus-erythematosus-like syndrome, are due to hypersensitivity (allergic) reactions (1). Although most of these drug-induced hypersensitivities have been presumed to be mediated by immunogens formed by the covalent interaction of a reactive drug metabolite with tissue carrier macromolecules (2-6), it is only in the case ofhepatitis caused by the inhalation of anesthetic halothane that this mechanism has been supported substantially by experimental evidence.Previous studies have demonstrated that the majority of halothane hepatitis patients have unique serum antibodies that react with novel neoantigens in livers of animals (1,7,8) and humans (9) treated with halothane and have suggested that these neoantigens may play an immunopathological role in development of the patients' liver damage. Characterization of these neoantigens by immunoblotting with haptenspecific anti-trifluoroacetyl (TFA) antibodies and sera from several halothane hepatitis patients has revealed that they correspond to distinct liver microsomal protein fractions (100 kDa, 76 kDa, 59 kDa, 57 kDa, 54 kDa) (10, 11) that have been covalently modified by the reactive TFA halide metabolite of halothane (11).To investigate the role of the halothane-induced neoantigens in the pathogenesis of halothane hepatitis, a general approach for their purification and characterization has been developed and utilized to identify one of them. MATERIALS AND METHODSPurification of 59-kDa-TFA Protein from Hal...

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Section: Methodsmentioning

confidence: 99%

Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase.

Satoh

Martin

Schulick

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

126

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“…195,197) For maximal rates of catalysis, LPL requires apoC-II. 189) ApoC-II does not increase the binding of LPL to a lipid surface. 189) LPL is capable of hydrolyzing TG present in the PL monolayer.…”

Section: )mentioning

confidence: 99%

“…200) In the rare autosomal recessive disorder of familial LPL deficiency (type I hyperlipoproteinemia), the near absence of LPL activity results in fasting hypertriglyceridemia. 189) Heterozygotes for LPL deficiency have abnormalities in postprandial lipemia despite relatively normal fasting TG.…”

Section: )mentioning

confidence: 99%

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Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

Morita

2016

Biological & Pharmaceutical Bulletin

133

108

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Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.

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“…In fact, the mass of phospholipid and triglyceride hydrolyzed by LPL are similar during the metabolism of triglyceride-rich lipoproteins (53). ApoC-II, an activator of LPL activity, would probably not be available intracellularly, but LPL retains considerable activity toward phospholipids in its absence (54,55). If LPL and insulin share the same secretory pathway, LPL could compete with phospholipase A2 for the same substrate.…”

Section: Table II Sequence Data From Rt-pcr Products Using Lpl-specifmentioning

confidence: 99%

Relative Hypoglycemia and Hyperinsulinemia in Mice with Heterozygous Lipoprotein Lipase (LPL) Deficiency

Marshall¹,

Tordjman²,

Host³

et al. 1999

Journal of Biological Chemistry

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Lipoprotein lipase (LPL) provides tissues with fatty acids, which have complex effects on glucose utilization and insulin secretion. To determine if LPL has direct effects on glucose metabolism, we studied mice with heterozygous LPL deficiency (LPL؉/؊). LPL؉/؊ mice had mean fasting glucose values that were up to 39 mg/dl lower than LPL؉/؉ littermates. Despite having lower glucose levels, LPL؉/؊ mice had fasting insulin levels that were twice those of ؉/؉ mice. Hyperinsulinemic clamp experiments showed no effect of genotype on basal or insulin-stimulated glucose utilization. LPL message was detected in mouse islets, INS-1 cells (a rat insulinoma cell line), and human islets. LPL enzyme activity was detected in the media from both mouse and human islets incubated in vitro. In mice, ؉/؊ islets expressed half the enzyme activity of ؉/؉ islets. Islets isolated from ؉/؉ mice secreted less insulin in vitro than ؉/؊ and ؊/؊ islets, suggesting that LPL suppresses insulin secretion. To test this notion directly, LPL enzyme activity was manipulated in INS-1 cells. INS-1 cells treated with an adeno-associated virus expressing human LPL had more LPL enzyme activity and secreted less insulin than adeno-associated virus-␤-galactosidase-treated cells. INS-1 cells transfected with an antisense LPL oligonucleotide had less LPL enzyme activity and secreted more insulin than cells transfected with a control oligonucleotide. These data suggest that islet LPL is a novel regulator of insulin secretion. They further suggest that genetically determined levels of LPL play a role in establishing glucose levels in mice. Lipoprotein lipase (LPL)1 catalyzes the rate-limiting step for clearance of triglycerides from the blood. Hydrolysis of lipoprotein-associated triglycerides in the capillary beds of peripheral tissues such as muscle and adipose tissue produces free fatty acids that are available for local uptake (1). LPL enzyme activity is probably the major factor controlling movement of exogenous fatty acids into peripheral tissues. The overexpression of LPL in mouse muscle (2) increases tissue lipid as well as mitochondria and peroxisomes, the sites of fatty acid metabolism. Mice with homozygous LPL deficiency (LPLϪ/Ϫ) (3, 4) die soon after birth with minimal tissue lipid. Mice deficient in adipose tissue LPL develop adipose tissue lipid stores but only by inducing de novo fatty acid biosynthesis from glucose (5). These results suggest that tissue lipid content plays important roles in normal physiology and that LPL is essential for the acquisition of exogenous fatty acids by tissues.Fatty acids and glucose compete as respiratory substrates in many tissues (6). In muscle, fatty acids inhibit glucose utilization and oxidation. In liver, fatty acids inhibit glucose oxidation and promote gluconeogenesis. In the pancreatic beta cell (7), fatty acids have complex effects that differ depending on the duration of exposure. Since LPL is the dominant provider of fatty acids to tissues and fatty acids alter insulin secretion and glucose utilizatio...

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Mechanism of action of lipoprotein lipase

Cited by 33 publications

References 65 publications

Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase.

Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase.

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

Relative Hypoglycemia and Hyperinsulinemia in Mice with Heterozygous Lipoprotein Lipase (LPL) Deficiency

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