Strom TB

References (4)

Title : Molecular genetic testing and measurement of levels of GPIHBP1 autoantibodies in patients with severe hypertriglyceridemia: The importance of identifying the underlying cause of hypertriglyceridemia - Strom_2023_J.Clin.Lipidol__
Author(s) : Strom TB , Tveita AA , Bogsrud MP , Leren TP
Ref : J Clin Lipidol , : , 2023
Abstract : BACKGROUND: Severe hypertriglyceridemia can be caused by pathogenic variants in genes encoding proteins involved in the metabolism of triglyceride-rich lipoproteins. A key protein in this respect is lipoprotein lipase (LPL) which hydrolyzes triglycerides in these lipoproteins. Another important protein is glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) which transports LPL to the luminal side of the endothelial cells. OBJECTIVE: Our objective was to identify a genetic cause of hypertriglyceridemia in 459 consecutive unrelated subjects with levels of serum triglycerides <=20 mmol/l. These patients had been referred for molecular genetic testing from 1998 to 2021. In addition, we wanted to study whether GPIHBP1 autoantibodies also were a cause of hypertriglyceridemia. METHODS: Molecular genetic analyses of the genes encoding LPL, GPIHBP1, apolipoprotein C2, lipase maturation factor 1 and apolipoprotein A5 as well as apolipoprotein E genotyping, were performed in all 459 patients. Serum was obtained from 132 of the patients for measurement of GPIHBP1 autoantibodies approximately nine years after molecular genetic testing was performed. RESULTS: A monogenic cause was found in four of the 459 (0.9%) patients, and nine (2.0%) patients had dyslipoproteinemia due to homozygosity for apolipoprotein E2. One of the 132 (0.8%) patients had GPIHBP1 autoantibody syndrome. CONCLUSION: Only 0.9% of the patients had monogenic hypertriglyceridemia, and only 0.8% had GPIHBP1 autoantibody syndrome. The latter figure is most likely an underestimate because serum samples were obtained approximately nine years after hypertriglyceridemia was first identified. There is a need to implement measurement of GPIHBP1 autoantibodies in clinical medicine to secure that proper therapeutic actions are taken.
ESTHER : Strom_2023_J.Clin.Lipidol__
PubMedSearch : Strom_2023_J.Clin.Lipidol__
PubMedID: 37981531

Title : Lysosomal acid lipase does not have a propeptide and should not be considered being a proprotein - Strom_2020_Proteins_88_440
Author(s) : Strom TB , Vinje T , Bjune K , da Costa LT , Laerdahl JK , Leren TP
Ref : Proteins , 88 :440 , 2020
Abstract : Lysosomal acid lipase (LAL) plays an important role in lipid metabolism by performing hydrolysis of triglycerides and cholesteryl esters in the lysosome. Based upon characteristics of LAL purified from human liver, it has been proposed that LAL is a proprotein with a 55 residue propeptide that may be essential for proper folding, intracellular transport, or enzymatic function. However, the biological significance of such a propeptide has not been fully elucidated. In this study, we have performed a series of studies in cultured HepG2 and HeLa cells to determine the role of the putative propeptide. However, by Western blot analysis and subcellular fractionation, we have not been able to identify a cleaved LAL lacking the N-terminal 55 residues. Moreover, mutating residues surrounding the putative cleavage site at Lys76 downward arrow in order to disrupt a proteinase recognition sequence, did not affect LAL activity. Furthermore, forcing cleavage at Lys76 downward arrow by introducing the optimal furin cleavage site RRRR downward arrowEL between residues 76 and 77, did not affect LAL activity. These data, in addition to bioinformatics analyses, indicate that LAL is not a proprotein. Thus, it is possible that the previously reported cleavage at Lys76 downward arrow could have resulted from exposure to proteolytic enzymes during the multistep purification procedure.
ESTHER : Strom_2020_Proteins_88_440
PubMedSearch : Strom_2020_Proteins_88_440
PubMedID: 31587363
Gene_locus related to this paper: human-LIPA

Title : Characterization of the mechanisms by which missense mutations in the lysosomal acid lipase gene disrupt enzymatic activity - Vinje_2019_Hum.Mol.Genet_28_3043
Author(s) : Vinje T , Laerdahl JK , Bjune K , Leren TP , Strom TB
Ref : Hum Mol Genet , 28 :3043 , 2019
Abstract : Hydrolysis of cholesteryl esters and triglycerides in the lysosome is performed by lysosomal acid lipase (LAL). In this study we have investigated how 23 previously identified missense mutations in the LAL gene (LIPA) (OMIM# 613497) affect the structure of the protein and thereby disrupt LAL activity. Moreover, we have performed transfection studies to study intracellular transport of the 23 mutants. Our main finding was that most pathogenic mutations result in defective enzyme activity by affecting the normal folding of LAL. Whereas, most of the mutations leading to reduced stability of the cap domain did not alter intracellular transport, nearly all mutations that affect the stability of the core domain gave rise to a protein that was not efficiently transported from the endoplasmic reticulum (ER) to the Golgi apparatus. As a consequence, ER stress was generated that is assumed to result in ER-associated degradation of the mutant proteins. The two LAL mutants Q85K and S289C were selected to study whether secretion-defective mutants could be rescued from ER-associated degradation by the use of chemical chaperones. Of the five chemical chaperones tested, only the proteasomal inhibitor MG132 markedly increased the amount of mutant LAL secreted. However, essentially no increased enzymatic activity was observed in the media. These data indicate that the use of chemical chaperones to promote the exit of folding-defective LAL mutants from the ER, may not have a great therapeutic potential as long as these mutants appear to remain enzymatically inactive.
ESTHER : Vinje_2019_Hum.Mol.Genet_28_3043
PubMedSearch : Vinje_2019_Hum.Mol.Genet_28_3043
PubMedID: 31131398
Gene_locus related to this paper: human-LIPA

Title : Prevalence of cholesteryl ester storage disease among hypercholesterolemic subjects and functional characterization of mutations in the lysosomal acid lipase gene - Vinje_2018_Mol.Genet.Metab_123_169
Author(s) : Vinje T , Wierod L , Leren TP , Strom TB
Ref : Mol Genet Metab , 123 :169 , 2018
Abstract : Lysosomal acid lipase hydrolyzes cholesteryl esters and triglycerides contained in low density lipoprotein. Patients who are homozygous or compound heterozygous for mutations in the lysosomal acid lipase gene (LIPA), and have some residual enzymatic activity, have cholesteryl ester storage disease. One of the clinical features of this disease is hypercholesterolemia. Thus, patients with hypercholesterolemia who do not carry a mutation as a cause of autosomal dominant hypercholesterolemia, may actually have cholesteryl ester storage disease. In this study we have performed DNA sequencing of LIPA in 3027 hypercholesterolemic patients who did not carry a mutation as a cause of autosomal dominant hypercholesterolemia. Functional analyses of possibly pathogenic mutations and of all mutations in LIPA listed in The Human Genome Mutation Database were performed to determine the pathogenicity of these mutations. For these studies, HeLa T-REx cells were transiently transfected with mutant LIPA plasmids and Western blot analysis of cell lysates was performed to determine if the mutants were synthesized in a normal fashion. The enzymatic activity of the mutants was determined in lysates of the transfected cells using 4-methylumbelliferone-palmitate as the substrate. A total of 41 mutations in LIPA were studied, of which 32 mutations were considered pathogenic by having an enzymatic activity <10% of normal. However, none of the 3027 hypercholesterolemic patients were homozygous or compound heterozygous for a pathogenic mutation. Thus, cholesteryl ester storage disease must be a very rare cause of hypercholesterolemia in Norway.
ESTHER : Vinje_2018_Mol.Genet.Metab_123_169
PubMedSearch : Vinje_2018_Mol.Genet.Metab_123_169
PubMedID: 29196158
Gene_locus related to this paper: human-LIPA