Novel ENU-induced point mutation in scavenger receptor class B, member 1, results in liver specific loss of SCARB1 protein.
Cardiovascular disease (CVD) is the largest cause of premature death in human populations throughout the world. Circulating plasma lipid levels, specifically high levels of LDL or low levels of HDL, are predictive of susceptibility to CVD. The scavenger receptor class B member 1 (SCARB1) is the primary receptor for the selective uptake of HDL cholesterol by liver and steroidogenic tissues. Hepatic SCARB1 influences plasma HDL-cholesterol levels and is vital for reverse cholesterol transport. Here we describe the mapping of a novel N-ethyl-N-nitrosourea (ENU) induced point mutation in the Scarb1 gene identified in a C57BL/6J background. The mutation is located in a highly conserved amino acid in the extracellular loop and leads to the conversion of an isoleucine to an asparagine (I179N). Homozygous mutant mice express normal Scarb1 mRNA levels and are fertile. SCARB1 protein levels are markedly reduced in liver (approximately 90%), but not in steroidogenic tissues. This leads to approximately 70% increased plasma HDL levels due to reduced HDL cholesteryl ester selective uptake. Pdzk1 knockout mice have liver-specific reduction of SCARB1 protein as does this mutant; however, in vitro analysis of the mutation indicates that the regulation of SCARB1 protein in this mutant is independent of PDZK1. This new Scarb1 model may help further our understanding of post-translational and tissue-specific regulation of SCARB1 that may aid the important clinical goal of raising functional HDL.
Stylianou
Ioannis M
IM
School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. ist@mail.med.upenn.edu
Svenson
Karen L
KL
VanOrman
Sara K
SK
Langle
Yanina
Y
Millar
John S
JS
Paigen
Beverly
B
Rader
Daniel J
DJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017124:Conserved Sequence; D017931:DNA Primers; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D005298:Fertility; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology*; D010641:Phenotype; D017354:Point Mutation; D051122:Scavenger Receptors, Class B / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D008055:Lipids; D009153:Mutagens; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D005038:Ethylnitrosourea