NPC1 late endosomes contain elevated levels of non-esterified (‘free’) fatty acids and an abnormally glycosylated form of the NPC2 protein

Chen, Fannie W.; Gordon, Ronald E.; Ioannou, Yiannis A.

doi:10.1042/bj20050236

Cited by 55 publications

(55 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 Ϫ/Ϫ liver, late endocytic organelles contain elevated levels of free fatty acids, suggesting that lysosomal fatty acid egress may be impaired. 9 However, in the fibroblasts of patients with NPC1, the flux of fatty acids through lysosomes was normal. 10 There is also little information on the effects of NPC1 on blood lipids in humans.…”

Section: Methods and Results-in Npc1mentioning

confidence: 99%

“…In Npc1 ϩ/Ϫ macrophages, the incorporation of lipoprotein-derived fatty acids into phospholipids was inhibited, 28 and late endosomes from Npc1 Ϫ/Ϫ mouse liver contained elevated levels of free fatty acids. 9 However, in NPC1 patient fibroblasts, the fatty acid flux through lysosomes was normal. 10 Therefore, we assessed the metabolism of LDL-derived oleic acid in Npc1 Ϫ/Ϫ hepatocytes similarly as in fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Niemann-Pick C1 Modulates Hepatic Triglyceride Metabolism and Its Genetic Variation Contributes to Serum Triglyceride Levels

Uronen

Lundmark²,

Orho‐Melander

et al. 2010

ATVB

View full text Add to dashboard Cite

Objective-To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels. Methods and Results-In Npc1Ϫ/Ϫ mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1 Ϫ/Ϫ mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. Ϫ/Ϫ hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest Pϭ8.7ϫ10Ϫ4 for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals. Key Words: dyslipidemia Ⅲ fatty liver Ⅲ lipid droplets Ⅲ lysosomal storage disease Ⅲ single-nucleotide polymorphism N iemann-Pick disease type C (NPC) is a rare autosomal recessive lipidosis, with most patients characterized by progressive neurological disease developing in late childhood. Patients suffering from the neonatal disease typically die of liver failure by the age of 6 months, and most patients with milder disease experience liver dysfunction. 1 More than 95% of the cases result from mutations in the NPC1 gene that encodes a large integral membrane protein of late endocytic organelles. The NPC1 protein is thought to be involved in the export of cholesterol and/or other lipids from these organelles. In the absence of NPC1 function, the cholesterol homeostatic machinery in the endoplasmic reticulum fails to sense the increased cholesterol levels, and cholesterol biosynthesis and uptake are inappropriately increased. 1,2 The liver plays a key role in the maintenance of whole body lipid balance. Hepatocytes take up cholesterol and triacylglycerols (triglycerides [TGs]), in particular via endocytosis of low-density lipoproteins (LDLs) and of chylomicron remnants postprandially, 3 and secrete cholesterol and TG in very-low density lipoproteins (VLDLs). 4 When there is an excess of lipid, lipid droplets provide a cytoplasmic deposit for TG and fatty acid esters of cholesterol (cholesteryl esters [CEs]). The Npc1 Ϫ/Ϫ mouse develops a liver disease similar to that in infants with NPC and provides a model for studying hepatic dysfunction in the disease. 5,6 In Npc1 Ϫ/Ϫ mouse liver, LDL uptake and cholesterol biosynthesis are increased. 7 The role of NPC1 in cholesterol homeostasis has received considerable attention; however, whether NPC1 contributes to TG metabolism is largely unexplored. In Npc1 Ϫ/Ϫ mice, a reduced TG content was found in the liver 5 and in isolated hepatocytes. 8 Ϫ/Ϫ liver, late endocytic organelles contain elevated levels of free fatty acids, suggesting that lysosomal fatty acid egress may be impaired. 9 However, in the fibroblasts of patients with NPC1, the flux of fatty acids...

show abstract

Section: Methods and Results-in Npc1mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Niemann-Pick C1 Modulates Hepatic Triglyceride Metabolism and Its Genetic Variation Contributes to Serum Triglyceride Levels

Uronen

Lundmark²,

Orho‐Melander

et al. 2010

ATVB

View full text Add to dashboard Cite

show abstract

“…Studies indicate that the NPC1 protein is expressed in all tissues and has a central role in regulating the transport of lipoprotein-derived lipid (cholesterol and fatty acids) from late endosomes and lysosomes to other cellular compartments to maintain cellular, tissue, and whole body lipid homeostasis [19][20][21] . The physiological mechanisms describing how NPC1 loss-of-function mutations or polymorphisms predispose to either NPC1 disease or common metabolic diseases (obesity and diabetes) remain undefined.…”

Section: Introductionmentioning

confidence: 99%

Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes

Garver¹

2015

J Diabetes Obes

View full text Add to dashboard Cite

A genome-wide association study (GWAS) and subsequent replication studies in diverse ethnic groups indicate that common Niemann-Pick C1 gene (NPC1) polymorphisms are associated with morbid-adult obesity or diabetes independent of body weight. The objectives for this prospective cross-sectional study were to determine allele frequencies for NPC1 polymorphisms (644A>G, 1926C>G, 2572A>G, and 3797G>A) and association with metabolic disease phenotypes in an ethnically diverse New Mexican obstetric population. Allele frequencies for 1926C>G, 2572A>G, and 3797G>A were significantly different between race/ethnic groups (non-Hispanic white, Hispanic, and Native American). The results also indicated a significant pairwise linkagedisequilibrium between each of the four NPC1 polymorphisms in race/ethnic groups. Moreover, the derived and major allele for 1926C>G was associated (OR 2.11, 95% CI 1.10-3.96, P = 0.022) with increased risk for maternal prepregnancy overweight (BMI 25.0-29.9kg/m 2 ) while the ancestral and major allele for 2572A>G was associated (OR 4.68, 95% CI 1.23-17.8, P = 0.024) with increased risk for gestational diabetes in non-Hispanic whites, but not Hispanics or Native Americans. In summary, this is the first transferability study to investigate common NPC1 polymorphisms in a multiethnic population and demonstrate a differential association with increased risk for maternal prepregnancy overweight and gestational diabetes. This is an Open access article distributed under the terms of Creative Commons Attribution 4.0 International License.

show abstract

“…An increase in the apparent molecular weight of single lysosomal proteins had been described in mouse models for lysosomal storage diseases, e.g., recently for cathepsin D in a mucolipidosis II model (18) and interestingly also for NPC2 protein in the NPC1 protein model, where it was shown to be hyperglycosylation (10). In the latter instance it was discussed as being the result of a trafficking/processing defect.…”

Section: Discussionmentioning

confidence: 96%

Impaired Lysosomal Trimming of N-Linked Oligosaccharides Leads to Hyperglycosylation of Native Lysosomal Proteins in Mice with α-Mannosidosis

Damme

Morelle

Schmidt

et al. 2010

Molecular and Cellular Biology

View full text Add to dashboard Cite

␣-Mannosidosis is caused by the genetic defect of the lysosomal ␣-D-mannosidase (LAMAN), which is involved in the breakdown of free ␣-linked mannose-containing oligosaccharides originating from glycoproteins with N-linked glycans, and thus manifests itself in an extensive storage of mannose-containing oligosaccharides. Here we demonstrate in a model of mice with ␣-mannosidosis that native lysosomal proteins exhibit elongated N-linked oligosaccharides as shown by two-dimensional difference gel electrophoresis, deglycosylation assays, and mass spectrometry. The analysis of cathepsin B-derived oligosaccharides revealed a hypermannosylation of glycoproteins in mice with ␣-mannosidosis as indicated by the predominance of extended Man3GlcNAc2 oligosaccharides. Treatment with recombinant human ␣-mannosidase partially corrected the hyperglycosylation of lysosomal proteins in vivo and in vitro. These data clearly demonstrate that LAMAN is involved not only in the lysosomal catabolism of free oligosaccharides but also in the trimming of asparaginelinked oligosaccharides on native lysosomal proteins.The lysosomal ␣-D-mannosidase (LAMAN; EC 3.2.1.24) belongs to the group of at least seven lysosomal exoglycosidases which sequentially degrade oligosaccharides derived from glycoproteins (2, 31). These glycoproteins enter the lysosomal compartment by either endocytic pathways (extracellular and plasma membrane proteins) or autophagic processes (intracellular proteins). In addition, free oligosaccharides originating from lipid-linked oligosaccharides in the endoplasmic reticulum and from glycoproteins by the endoplasmic reticulumassociated protein degradation (ERAD) pathway are transported into the lysosome, where these oligosaccharides are subsequently degraded (9, 45). Inside the lysosome, the degradation of the glycoproteins is described as a bidirectional process in which on the one hand the polypeptide is hydrolyzed by a cohort of lysosomal endo-and exoproteases with partially overlapping specificities like cathepsins and other peptidases 40,52). On the other hand, the sugar moiety is stepwise hydrolyzed into its monosaccharides by exoglycosidases. The precise order of the bidirectional breakdown of glycoproteins is unclear, although assumptions can be made based on the analysis of the storage products of the different glycoproteinoses (31). Therefore, it is assumed that an efficient degradation of the oligosaccharide chain is highly dependent on the cleavage of the protein-oligosaccharide linkage by the glycosylasparaginase (2, 31). In contrast, the proteolysis of the polypeptide backbone is mainly unaffected by intact oligosaccharide structures on the glycoproteins (1).LAMAN has a broad substrate specificity, cleaving nonreducing terminal ␣1,2-, ␣1,3-, and ␣1,6-mannosyl linkages found in complex-type, hybrid-type, and high-mannose-type asparagine-linked glycans (30, 60). Additionally, a second lysosomal mannosidase (MAN2B2) specific for the core ␣1,6 branch was characterized and found to be dependent on the prior enzymati...

show abstract

NPC1 late endosomes contain elevated levels of non-esterified (‘free’) fatty acids and an abnormally glycosylated form of the NPC2 protein

Cited by 55 publications

References 60 publications

Niemann-Pick C1 Modulates Hepatic Triglyceride Metabolism and Its Genetic Variation Contributes to Serum Triglyceride Levels

Niemann-Pick C1 Modulates Hepatic Triglyceride Metabolism and Its Genetic Variation Contributes to Serum Triglyceride Levels

Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes

Impaired Lysosomal Trimming of N-Linked Oligosaccharides Leads to Hyperglycosylation of Native Lysosomal Proteins in Mice with α-Mannosidosis

Contact Info

Product

Resources

About