piperidines and Abetalipoproteinemia

The microsomal triglyceride transfer protein (MTP) is necessary for the proper assembly of the apolipoprotein B containing lipoproteins, very low density lipoprotein and chylomicrons. Recent research has significantly advanced our understanding of the role of MTP in these pathways at the molecular and cellular level. Biochemical studies suggest that initiation of lipidation of the nascent apolipoprotein B polypeptide may occur through a direct association with MTP. This early lipidation may be required to allow the nascent polypeptide to fold properly and therefore avoid ubiquitination and degradation. Concerning the addition of core neutral lipids in the later stages of lipoprotein assembly, cell culture studies show that MTP lipid transfer activity is not required for this to occur for apolipoprotein B-100 containing lipoproteins. Likewise, MTP does not appear to directly mediate addition of core neutral lipid to nascent apoB-48 particles. However, new data indicate that MTP is required to produce triglyceride rich droplets in the smooth endoplasmic reticulum which may supply the core lipids for conversion of nascent, dense apoB-48 particles to mature VLDL. In addition, assembly of dense apolipoprotein B-48 containing lipoproteins has been observed in mouse liver in the absence of MTP. As a result of these new data, an updated model for the role of MTP in lipoprotein assembly is proposed.

Topics: Abetalipoproteinemia; Animals; Apolipoproteins B; Carrier Proteins; Cell Line; Cholesterol Ester Transfer Proteins; Endoplasmic Reticulum; Glycoproteins; Humans; Indoles; Lipoproteins; Lipoproteins, VLDL; Liver; Mice; Mice, Knockout; Microsomes; Nervous System; Piperidines; Protein Binding; Protein Folding; Yolk Sac

Topics: Abetalipoproteinemia; Carbazoles; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

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