A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein
Year: 2020
Type: article
Abstract: Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.
Source: PLoS Genetics
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Foundation for the National Institutes of Health, U.S. Department of Veterans Affairs, American Heart Association, G. Harold and Leila Y. Mathers Charitable Foundation, Wellcome Trust, Academy of Finland, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Effects of miR-30c deficiency on plasma cholesterol and atherosclerosis, G203482354, G2471424637, G2592540266, Mechanisms of cytoplasmic lipid droplet regulation in the intestine, G3787607271, Acquisition of GE Typhoon FLA9500 Variable Mode Imager, Mapping MTP lipid transfer activities for better therapeutics, G4976292069, In vivo HTS assay for novel modulators, G5068228932, G5388152886, Role Of Microsomal Triglyceride Transfer Protein In Adipose Tissue, Discovery and characterization of novel regulators of Apo-B in larval zebrafish, G5678557786, Molecular mechanisms of chylomicron assembly, Role of Lipoprotein Assembly in Maternal-Fetal Transport of Beta-Carotene, G6504515028, G675588505, G7086285712, G7105783532, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers., Circadian Regulation of Lipoprotein Assembly, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers, G9000094951, G9000190761, G9000237333, G9000269549, Systematic Vertebrate Functional Genomics, Cellular and Molecular Biology, Identifying genes required for digestive physiology and lipid metabolism
OpenAlex ID: W3046981728