A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein


Autoři: Meredith H. Wilson aff001;  Sujith Rajan aff002;  Aidan Danoff aff001;  Richard J. White aff004;  Monica R. Hensley aff001;  Vanessa H. Quinlivan aff001;  Rosario Recacha aff006;  James H. Thierer aff001;  Frederick J. Tan aff001;  Elisabeth M. Busch-Nentwich aff004;  Lloyd Ruddock aff006;  M. Mahmood Hussain aff002;  Steven A. Farber aff001
Působiště autorů: Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland, United States of America aff001;  New York University Long Island School of Medicine, Mineola, New York, United States of America aff002;  Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America aff003;  Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom aff004;  Cambridge Institute of Therapeutic Immunology & Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, United Kingdom aff005;  Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland aff006
Vyšlo v časopise: A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008941
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008941

Souhrn

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.

Klíčová slova:

Embryos – Fatty liver – Gastrointestinal tract – Immunoprecipitation – Lipids – Lipoproteins – Missense mutation – Zebrafish


Zdroje

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