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BMC Medical Genetics Oct 2015Microsomal triglyceride transfer protein (MTP) works to lipidate and assemble the apoB-containing lipoproteins in liver. It closely links up the hepatic secretion of...
BACKGROUND
Microsomal triglyceride transfer protein (MTP) works to lipidate and assemble the apoB-containing lipoproteins in liver. It closely links up the hepatic secretion of lipid to regulate serum lipid and atherosclerosis. Cases of MTTP gene mutation is characterized by abetalipoproteinemia and remarkable hepatic steatosis or cirrhosis. Several MTTP polymorphisms have been reported relating to metabolic syndrome, hyperlipidemia and steatohepatitis. We supposed the regulation of serum lipids and risk of non-alcoholic fatty liver disease (NAFLD) formation may be modified by individual susceptibility related to the MTTP polymorphisms.
METHODS AND RESULTS
A cross-sectional population of 1193 subjects, 1087 males and 106 females mean aged 45.9 ± 8.9 years, were enrolled without recognized secondary hyperlipidemia. Fasting serum lipid, insulin, and non-esterified fatty acid were assessed and transformed to insulin resistance index, HOMA-IR and Adipo-IR. After ruling out alcohol abuser, non-alcoholic fatty liver disease (NAFLD) was diagnosed by abdominal ultrasound. Five common MTTP polymorphisms (promoter -493 G/T, E98D, I128T, N166S, and Q297H) were conducted by TaqMan assay. Multivariate regression analysis was used to estimate their impact on serum lipid and NAFLD risk. Assessment revealed a differential impact on LDL-C and non-HDL-C, which were sequentially determined by the Q297H polymorphism, insulin resistance, body mass index and age. Carriers of homozygous minor allele (297 H) had significantly lower LDL-C and non-HDL-C but higher risk for NAFLD. Molecular modeling of the 297 H variant demonstrated higher free energy, potentially referring to an unstable structure and functional sequence.
CONCLUSION
These results evidenced the MTTP polymorphisms could modulate the lipid homeostasis to determine the serum lipids and risk of NAFLD. The MTTP 297 H polymorphism interacted with age, insulin resistance and BMI to decrease serum apoB containing lipoproteins (LDL-C and non-HDL-C) but increase the risk of NAFLD formation.
Topics: Adult; Carrier Proteins; Cholesterol; Cross-Sectional Studies; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Models, Molecular; Non-alcoholic Fatty Liver Disease; Polymorphism, Single Nucleotide; Protein Structure, Secondary; Ultrasonography
PubMed: 26458397
DOI: 10.1186/s12881-015-0242-6 -
Middle East Journal of Digestive... Jul 2015Abetalipoproteinemia (ABL) is a very rare autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein gene (MTTP). ABL is...
Abetalipoproteinemia (ABL) is a very rare autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein gene (MTTP). ABL is characterized by lack of lipids and apolipoprotein B (apoB) in plasma, fat malabsorption and various clinical manifestations. We describe a 12-month-old infant boy, born from consanguineous parents and presented with diarrhea, steatorrhea, growth retardation, hypothyroidism, intraventricular brain cyst and kidney stones. The patient was diagnosed to have ABL and treated with dietary modification and oral fat-soluble vitamin replacement and followed until he reached 5 years of age.
PubMed: 26396722
DOI: No ID Found -
The Journal of Biological Chemistry Oct 2015Sphingolipids, a large family of bioactive lipids, are implicated in stress responses, differentiation, proliferation, apoptosis, and other physiological processes....
Sphingolipids, a large family of bioactive lipids, are implicated in stress responses, differentiation, proliferation, apoptosis, and other physiological processes. Aberrant plasma levels of sphingolipids contribute to metabolic disease, atherosclerosis, and insulin resistance. They are fairly evenly distributed in high density and apoB-containing lipoproteins (B-lps). Mechanisms involved in the transport of sphingolipids to the plasma are unknown. Here, we investigated the role of microsomal triglyceride transfer protein (MTP), required for B-lp assembly and secretion, in sphingolipid transport to the plasma. Abetalipoproteinemia patients with deleterious mutations in MTP and absence of B-lps had significantly lower plasma ceramide and sphingomyelin but normal hexosylceramide, lactosylceramide, and different sphingosines compared with unaffected controls. Furthermore, similar differential effects on plasma sphingolipids were seen in liver- and intestine-specific MTP knock-out (L,I-Mttp(-/-)) mice, suggesting that MTP specifically plays a role in the regulation of plasma ceramide and sphingomyelin. We hypothesized that MTP deficiency may affect either their synthesis or secretion. MTP deficiency had no effect on ceramide and sphingomyelin synthesis but reduced secretion from primary hepatocytes and hepatoma cells. Therefore, MTP is involved in ceramide and sphingomyelin secretion but not in their synthesis. We also found that MTP transferred these lipids between vesicles in vitro. Therefore, we propose that MTP might regulate plasma ceramide and sphingomyelin levels by transferring these lipids to B-lps in the liver and intestine and facilitating their secretion.
Topics: Animals; Carrier Proteins; Cell Line; Ceramides; Humans; Male; Mice; Mice, Inbred C57BL; Sphingomyelins
PubMed: 26350457
DOI: 10.1074/jbc.M115.659110 -
Circulation. Cardiovascular Genetics Oct 2015The use of microsomal triglyceride transfer protein (MTP) inhibitors is limited to severe hyperlipidemias because of associated hepatosteatosis and gastrointestinal...
BACKGROUND
The use of microsomal triglyceride transfer protein (MTP) inhibitors is limited to severe hyperlipidemias because of associated hepatosteatosis and gastrointestinal adverse effects. Comprehensive knowledge about the structure-function of MTP might help design new molecules that avoid steatosis. Characterization of mutations in MTP causing abetalipoproteinemia has revealed that the central α-helical and C-terminal β-sheet domains are important for protein disulfide isomerase binding and lipid transfer activity. Our aim was to identify and characterize mutations in the N-terminal domain to understand its function.
METHODS AND RESULTS
We identified a novel missense mutation (D169V) in a 4-month-old Turkish male child with severe signs of abetalipoproteinemia. To study the effect of this mutation on MTP function, we created mutants via site-directed mutagenesis. Although D169V was expressed in the endoplasmic reticulum and interacted with apolipoprotein B (apoB) 17, it was unable to bind protein disulfide isomerase, transfer lipids, and support apoB secretion. Computational modeling suggested that D169 could form an internal salt bridge with K187 and K189. Mutagenesis of these lysines to leucines abolished protein disulfide isomerase heterodimerization, lipid transfer, and apoB secretion, without affecting apoB17 binding. Furthermore, mutants with preserved charges (D169E, K187R, and K189R) rescued these activities.
CONCLUSIONS
D169V is detrimental because it disrupts an internal salt bridge leading to loss of protein disulfide isomerase binding and lipid transfer activities; however, it does not affect apoB binding. Thus, the N-terminal domain of MTP is also important for its lipid transfer activity.
Topics: Abetalipoproteinemia; Animals; Apolipoproteins B; Binding Sites; COS Cells; Carrier Proteins; Chlorocebus aethiops; DNA Mutational Analysis; Endoplasmic Reticulum; Humans; Infant; Lipid Metabolism; Male; Mutation, Missense; Protein Binding; Protein Structure, Tertiary; Transfection
PubMed: 26224785
DOI: 10.1161/CIRCGENETICS.115.001106 -
American Journal of Hematology Feb 2016
Topics: Abetalipoproteinemia; Acanthocytes; Atorvastatin; Female; Hemolysis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged
PubMed: 26147873
DOI: 10.1002/ajh.24105 -
PloS One 2015Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate...
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pantothenate kinases catalyze the rate-limiting step of coenzyme A synthesis and Pank2 is the only pantothenate kinase isoform in humans that is localized to mitochondria. Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations. In this study, we analyzed acanthocytosis of a cohort of 25 PKAN patients from the Dominican Republic that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wild-type with respect to this mutation. 3D modeling of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (6-10%) or no (<6%) acanthocytosis. Heterozygous control donors revealed a tendency to mild acanthocytosis. Based on the insight that Pank2 is a normal constituent of red blood cells and de novo biosynthesis of coenzyme A is likely to take place in the erythrocyte cytosol we propose a hypothetical model that accounts for the variability in the occurrence of acanthocytic cells in PKAN.
Topics: Abetalipoproteinemia; Acanthocytes; Adolescent; Adult; Child; Cohort Studies; Dominican Republic; Enzyme Stability; Homozygote; Humans; Models, Molecular; Pantothenate Kinase-Associated Neurodegeneration; Phosphotransferases (Alcohol Group Acceptor); Polymorphism, Single Nucleotide; Young Adult
PubMed: 25915509
DOI: 10.1371/journal.pone.0125861 -
JIMD Reports 2015Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare inherited forms of hypolipidemia. Their differential diagnosis is important for...
BACKGROUND
Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare inherited forms of hypolipidemia. Their differential diagnosis is important for predicting of the prognosis and selecting appropriate therapy.
MATERIALS AND METHODS
Genetic analysis was performed in two patients with primary hypocholesterolemia born from consanguineous parents. The oral fat tolerance test (OFTT) was performed in one patient with FHBL (apoB-87.77) and one with ABL as well as in four normal control subjects. After overnight fasting, blood samples were drawn. Serum lipoprotein and remnant-like particle (RLP) fractions were determined by HPLC analysis.
RESULTS
Both patients with homozygous FHBL were asymptomatic probably because of preserved levels of fat-soluble vitamins, especially vitamin E. The patients with FHBL were homozygous because of novel apoB-83.52 and apoB-87.77 mutations, and although one of them (apoB-87.77) had fatty liver disease, microscopic findings suggesting nonalcoholic steatohepatitis were absent. Fasting apoB-48 and RLP-triglyceride levels in the patient with homozygous FHBL, which were similar to those in normal control subjects, increased after OFTT both in normal control subjects and the patient with FHBL but not in the patient with ABL, suggesting that the fat load administered was absorbed only in the patient with FHBL.
CONCLUSION
Although lipid levels in the patients with homozygous FHBL and ABL were comparable, fasting, postoral fat loading of apoB-48, as well as RLP-triglyceride levels, may help in the differential diagnosis of FHBL and ABL and provide a prompt diagnosis using genetic analysis in the future.
PubMed: 25763510
DOI: 10.1007/8904_2015_415 -
Circulation Research Jan 2015The microsomal triglyceride transfer protein (MTP), the product of the MTTP gene, is essential for the assembly and secretion of apolipoprotein B-containing... (Review)
Review
The microsomal triglyceride transfer protein (MTP), the product of the MTTP gene, is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins, but when defective causes abetalipoproteinemia. Abetalipoproteinemia is a rare autosomal recessive disorder characterized by the inability to produce chylomicrons or very low-density lipoproteins, with the absence of apolipoprotein B-containing lipoproteins in the circulation. Knowledge of the molecular basis for abetalipoproteinemia has led to the development of therapies for dyslipidemia that inhibit MTP. Partial MTP inhibition using small molecule inhibitors, such as lomitapide, can effectively lower plasma low-density lipoprotein-cholesterol and apolipoprotein B levels, but is associated with gastrointestinal side effects and hepatic steatosis, whose long-term sequelae remain unclear; lomitapide has accordingly only been approved as a treatment for homozygous familial hypercholesterolemia. Intestine-specific inhibitors of MTP decrease chylomicron biogenesis and improve insulin sensitivity in experimental animals and, while overcoming hepatic steatosis, may have significant gastrointestinal side effects that could limit their use in humans. We review contemporary aspects of the biology and therapeutic regulation of MTP and their significance for lipid metabolism and cardiovascular disease.
Topics: Abetalipoproteinemia; Animals; Benzimidazoles; Carrier Proteins; Genetic Therapy; Humans; Lipid Metabolism; Protein Structure, Secondary
PubMed: 25552696
DOI: 10.1161/CIRCRESAHA.116.304637 -
BMJ Case Reports Dec 2014Abetalipoproteinemia is a rare metabolic disorder that causes disturbed lipid absorption with consequent hypocholesterolaemia and liposoluble avitaminosis. The broad... (Review)
Review
Abetalipoproteinemia is a rare metabolic disorder that causes disturbed lipid absorption with consequent hypocholesterolaemia and liposoluble avitaminosis. The broad spectrum of presentations includes malabsorption, failure to thrive and acanthocytosis in children, while later in life expected manifestations include coagulopathy, myopathy, retinitis pigmentosa, peripheral neuropathy, hyporeflexia and ataxia. These neurological complications stem from demyelination secondary to vitamin E deficiency. Another complication is reduced fertility in women. In the event of a successful conception, issues arise in vitamin supplementation, the mainstay of treatment of abetalipoproteinemia. The skilful clinician must master the delicate balance between the teratogenic effects on the fetus of over as well as under replacement of vitamins, pregnancy complications such as premature rupture of membranes and eclampsia, and, finally, maternal complications such as corneal ulcers. We describe the management of a patient ranging from pubertal growth to bearing a successful spontaneous pregnancy with an outcome of a completely healthy mother and child.
Topics: Abetalipoproteinemia; Adult; Dietary Supplements; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Gestational Age; Humans; Infant, Newborn; Maternal Age; Monitoring, Physiologic; Pregnancy; Pregnancy Outcome; Pregnancy, High-Risk; Term Birth; Vitamin A; Vitamin E; Vitamin K; Vitamins
PubMed: 25488886
DOI: 10.1136/bcr-2014-206754 -
Journal of Medical Case Reports Nov 2014Klippel-Trenaunay syndrome is a rare congenital mesodermal abnormality characterized by bone and soft tissue hypertrophy, extensive hemangioma and venous abnormalities....
INTRODUCTION
Klippel-Trenaunay syndrome is a rare congenital mesodermal abnormality characterized by bone and soft tissue hypertrophy, extensive hemangioma and venous abnormalities. We report the case of a patient with two additional rare clinical manifestations in the background of Klippel-Trenaunay syndrome, namely, acanthocytosis and splenic and retroperitoneal lymphangioma.
CASE PRESENTATION
A 24-year-old Sri Lankan man from North Central Province in Sri Lanka presented to our general medical unit with symptomatic anaemia. He had been diagnosed with Klippel-Trenaunay syndrome at the age of six years, with hemihypertrophy of his right lower limb and strawberry naevi over both lower limbs. His blood film results were positive for acanthocytes, which accounted for more than 20% of the red blood cell population. He was also found to have extensive splenic lymphangiomas and a large retroperitoneal lymphangioma encasing the mesentric vessels in the right para-aortic region. An extensive battery of tests to identify a secondary cause for the acanthocytosis failed to show any positive results.
CONCLUSIONS
Retroperitoneal lymphangioma has been reported in association with Klippel-Trenaunay syndrome once before, but an association with acanthocytosis has never been reported. Given the rarity of all three conditions this is not surprising. The cause of acanthocytosis in this setting is currently unresolved. It is plausible that this may be a primary association with Klippel-Trenaunay syndrome, as an alternative aetiology was not found.
Topics: Abetalipoproteinemia; Humans; Klippel-Trenaunay-Weber Syndrome; Lymphangioma; Male; Retroperitoneal Neoplasms; Spleen; Splenic Neoplasms; Tomography, X-Ray Computed; Young Adult
PubMed: 25427442
DOI: 10.1186/1752-1947-8-390