Atherogenic diet leads to posttranslational down-regulation of murine hepatocyte SR-BI expression.
The scavenger receptor class B, type I (SR-BI) mediates selective cholesteryl ester uptake by the liver and thereby exerts a systemic anti-atherogenic effect. It is unknown, however, whether exogenous cholesterol contributes to the regulation of hepatic SR-BI expression. Atherosclerosis resistant SJL and susceptible C57Bl/6 mice were challenged with atherogenic diets that lead to an increase of both plasma and liver cholesterol. The increase of cholesterol was accompanied by a marked posttranslational down-regulation of liver SR-BI expression. On average, we observed a threefold decrease of SR-BI protein while mRNA levels were slightly increased in both strains. Mice with transgenic over-expression of the sterol regulatory element binding proteins (SREBPs) were used as a model that displays endogenously increased liver cholesterol concentrations. In SREBP-1a and -1c transgenic mice on normal chow, SR-BI was transcriptionally down-regulated. When fed the atherogenic diet, the posttranslational SR-BI regulation was still functional on this background. Down-regulation of SR-BI did not alter the hepatocyte surface expression pattern, but was accompanied by a decrease of PDZK1, an adaptor protein recently identified to control SR-BI protein expression levels in the liver and intestine. Taken together, a diet-induced increase of plasma and hepatic cholesterol levels leads to a posttranscriptional down-regulation of SR-BI in mouse liver via a mechanism likely involving PDZK1.
Department of Biochemistry and Molecular Biology II, Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20249 Hamburg, Germany.
Andreas
A
Niemeier
Werner J
WJ
Kovacs
Wolfgang
W
Strobl
Herbert
H
Stangl
D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004036:Diet, Atherogenic; D015536:Down-Regulation; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011499:Protein Processing, Post-Translational
D018955:CD36 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; C514896:PDZK1 protein, mouse; D002784:Cholesterol