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JCI Insight Jul 2021Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs, and LDLs and is essential for their production. Defects in ApoB synthesis and secretion result in...
Apolipoprotein B (ApoB) is the primary protein of chylomicrons, VLDLs, and LDLs and is essential for their production. Defects in ApoB synthesis and secretion result in several human diseases, including abetalipoproteinemia and familial hypobetalipoproteinemia (FHBL1). In addition, ApoB-related dyslipidemia is linked to nonalcoholic fatty liver disease (NAFLD), a silent pandemic affecting billions globally. Due to the crucial role of APOB in supplying nutrients to the developing embryo, ApoB deletion in mammals is embryonic lethal. Thus, a clear understanding of the roles of this protein during development is lacking. Here, we established zebrafish mutants for 2 apoB genes: apoBa and apoBb.1. Double-mutant embryos displayed hepatic steatosis, a common hallmark of FHBL1 and NAFLD, as well as abnormal liver laterality, decreased numbers of goblet cells in the gut, and impaired angiogenesis. We further used these mutants to identify the domains within ApoB responsible for its functions. By assessing the ability of different truncated forms of human APOB to rescue the mutant phenotypes, we demonstrate the benefits of this model for prospective therapeutic screens. Overall, these zebrafish models uncover what are likely previously undescribed functions of ApoB in organ development and morphogenesis and shed light on the mechanisms underlying hypolipidemia-related diseases.
Topics: Animals; Apolipoproteins B; Embryonic Development; Endothelial Cells; Fatty Liver; Goblet Cells; Intestines; Models, Biological; Mutation; Neovascularization, Pathologic; Vascular Remodeling; Zebrafish; Zebrafish Proteins
PubMed: 34236046
DOI: 10.1172/jci.insight.130399 -
Cells Jun 2021Human microsomal triglyceride transfer protein (hMTP) plays an essential role in the assembly of apoB-containing lipoproteins, and has become an important drug target...
Human microsomal triglyceride transfer protein (hMTP) plays an essential role in the assembly of apoB-containing lipoproteins, and has become an important drug target for the treatment of several disease states, such as abetalipoproteinemia, fat malabsorption and familial hypercholesterolemia. hMTP is a heterodimer composed of a larger hMTPα subunit and a smaller hMTPβ subunit (namely, protein disulfide isomerase, hPDI). hPDI can interact with 17β-estradiol (E), an endogenous female sex hormone. It has been reported that E can significantly reduce the blood levels of low-density lipoprotein, cholesterol and triglyceride, and modulate liver lipid metabolism in vivo. However, some of the estrogen's actions on lipid metabolism are not associated with estrogen receptors (ER), and the exact mechanism underlying estrogen's ER-independent lipid-modulating action is still not clear at present. In this study, the potential influence of E on the stability of the hMTP complex is investigated by jointly using multiple molecular dynamics analyses based on available experimental structures. The molecular dynamics analyses indicate that the hMTP complex in the presence of E has reduced interface contacts and surface areas. A steered molecular dynamics analysis shows that the forces required to separate the two subunits (namely, hPDI and hMTPα subunit) of the hMTP complex in the absence of E are significantly higher than the forces required to separate the complex in which its hPDI is already bound with E. E makes the interface between hMTPα and hPDI subunits more flexible and less stable. The results of this study suggest that E-induced conformational changes of the hMTP complex might be a novel mechanism partly accounting for the ER-independent lipid-modulating effect of E.
Topics: Carrier Proteins; Estradiol; Humans; Molecular Dynamics Simulation; Protein Conformation; Protein Subunits; Thermodynamics
PubMed: 34206252
DOI: 10.3390/cells10071566 -
Journal of Investigative Medicine High... 2021Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the gene encoding the microsomal triglyceride transfer...
Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the gene encoding the microsomal triglyceride transfer protein large subunit. ABL is characterized by absence of apolipoprotein B-containing lipoproteins and deficiencies in fat-soluble vitamins leading to multisystem involvement of which neurological complications are the most serious. We present 3 siblings with ABL who were born to non-consanguineous parents of Filipino and Chinese background. Identical twin boys with long-standing failure to thrive and malabsorption were diagnosed at age 2 years. ABL therapy with vitamins and a specialized diet was initiated, replacing total parenteral nutrition at age 3 years. Their younger sister was diagnosed from a blood sample taken at birth; treatment was instituted shortly thereafter. We observed in the twins reversal and in their sister prevention of ABL systemic features following early implementation of fat restriction and high doses of oral fat-soluble vitamins. A targeted sequencing panel found that each affected sibling is homozygous for a novel intron 13 -2A>G splice acceptor site mutation, predicted to abolish splicing of intron 13. This variant brings to more than 60 the number of reported pathogenic mutations, which are summarized in this article. The twin boys and their sister are now doing well at 11 and 4 years of age, respectively. This experience underscores the importance of early initiation of targeted specialized dietary and fat-soluble vitamin replacements in ABL.
Topics: Abetalipoproteinemia; Child, Preschool; Humans; Infant, Newborn; Male; Mutation; Siblings; Thymine Nucleotides; Vitamin A
PubMed: 34078172
DOI: 10.1177/23247096211022484 -
Journal of Clinical Lipidology 2021"Normotriglyceridemic abetalipoproteinemia (ABL)" was originally described as a clinical entity distinct from either ABL or hypobetalipoproteinemia. Subsequent studies...
"Normotriglyceridemic abetalipoproteinemia (ABL)" was originally described as a clinical entity distinct from either ABL or hypobetalipoproteinemia. Subsequent studies identified mutations in APOB gene which encoded truncated apoB longer than apoB48. Therefore, "Normotriglyceridemic ABL" can be a subtype of homozygous familial hypobetalipoproteinemia. Here, we report an atypical female case of ABL who was initially diagnosed with "normotriglyceridemic ABL", because she had normal plasma apoB48 despite the virtual absence of apoB100 and low plasma TG level. Next generation sequencing revealed that she was a compound heterozygote of two novel MTTP mutations: nonsense (p.Q272X) and missense (p.G709R). We speculate that p.G709R might confer residual triglyceride transfer activity of MTTP preferentially in the intestinal epithelium to the hepatocytes, allowing production of apoB48. Together, "normotriglyceridemic ABL" may be a heterogenous disorder which is caused by specific mutations in either APOB or MTTP gene.
Topics: Abetalipoproteinemia; Adult; Aged; Apolipoprotein B-100; Apolipoprotein B-48; Biomarkers; Carrier Proteins; Female; Heterozygote; Humans; Male; Mutation
PubMed: 34052173
DOI: 10.1016/j.jacl.2021.04.013 -
Clinica E Investigacion En... May 2021Hypolipoproteinemias are characterized by a decrease in the plasma concentration of lipoproteins. Within them, we find two groups: hypobetalipoproteinemias (HBL), due to... (Review)
Review
Hypolipoproteinemias are characterized by a decrease in the plasma concentration of lipoproteins. Within them, we find two groups: hypobetalipoproteinemias (HBL), due to a decrease in the plasma concentration of lipoproteins containing apolipoprotein B, and hypoalphalipoproteinemias. Hypolipoproteinemias can be classified according to their origin, into primary and secondary. Primary HBLs are rare entities produced by mutations in different genes. So far, more than 140 mutations have been identified in the APOB, PCSK9, ANGPTL3, MTTP, and SAR1 genes. Early diagnosis and treatment are essential to avoid the development of serious complications. In this review we address the diagnosis and treatment of HBL, especially those in which there is hypotriglyceridemia.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Apolipoproteins B; Humans; Hypobetalipoproteinemias; Hypolipoproteinemias; Mutation; Proprotein Convertase 9
PubMed: 34006356
DOI: 10.1016/j.arteri.2020.12.011 -
Journal of Atherosclerosis and... Oct 2021Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride... (Review)
Review
Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) <15 mg/dL and apoB <15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.
Topics: Abetalipoproteinemia; Apolipoproteins B; Cholesterol, LDL; Cost of Illness; Disease Management; Humans; Prognosis
PubMed: 33994405
DOI: 10.5551/jat.RV17056 -
Journal of Pediatric Gastroenterology... Jul 2021Familial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result...
Familial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result in a defect in the synthesis or secretion of lipoproteins containing apolipoprotein B.In children, these conditions present with diarrhoea and growth failure, whereas adults present with neuromuscular, ophthalmological, and hepatic symptoms. Simple laboratory investigations have shown that diagnosis can be made from findings of dramatically decreased cholesterol levels, deficiencies in fat-soluble vitamins (mostly vitamin E), endoscopic findings of the characteristic white intestinal mucosa, and fat-loaded enterocytes in biopsy samples. Genetic analysis is used to confirm the diagnosis. Treatment is based on a low-fat diet with essential fatty acid supplementation, high doses of fat-soluble vitamins, and regular and life-long follow-up.The present study examines cases and literature findings of these conditions, and emphasises the need to explore severe hypocholesterolemia and deficiencies in fat-soluble vitamins to not miss these rare, but easy to diagnose and treat, disorders.
Topics: Abetalipoproteinemia; Adult; Apolipoproteins B; Child; Humans; Hypobetalipoproteinemias; Lipids; Vitamin E
PubMed: 33853111
DOI: 10.1097/MPG.0000000000003145 -
Pathology Aug 2021We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered...
We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.
Topics: Abetalipoproteinemia; Anaplastic Lymphoma Kinase; Anemia; Carbazoles; Carcinoma, Non-Small-Cell Lung; Hemolysis; Humans; Lung Neoplasms; Maleimides; Piperidines; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 33618863
DOI: 10.1016/j.pathol.2020.10.023 -
JPGN Reports Feb 2021Supplemental Digital Content is available in the text.
Supplemental Digital Content is available in the text.
PubMed: 37206948
DOI: 10.1097/PG9.0000000000000049 -
Gastroenterology May 2021
Topics: Abetalipoproteinemia; Apolipoprotein B-100; Female; Humans; Hyperlipidemia, Familial Combined; Hypobetalipoproteinemia, Familial, Apolipoprotein B; Hypobetalipoproteinemias; Malabsorption Syndromes; Pregnancy; Pregnancy Complications
PubMed: 33275938
DOI: 10.1053/j.gastro.2020.11.040