Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure.
BACKGROUND
Chronic renal failure (CRF) is associated with premature atherosclerosis, impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport, depressed clearance, and elevated plasma concentrations of very low-density lipoprotein (VLDL), chylomicrons, and their atherogenic remnants. LDL receptor-related protein (LRP) is a member of the LDL receptor gene family that is heavily expressed in the liver, and mediates removal of at least 30 different ligands, including VLDL remnants (IDL) and chylomicron remnants. This study was conducted to test the hypothesis that the well-known defect in clearance of IDL and chylomicron remnants in CRF may be indicative of diminished hepatic LRP abundance.


METHODS
Hepatic tissue LRP mRNA abundance [reverse transcription-polymerase chain reaction (RT-PCR)] and protein abundance (Western blot analysis) were determined in rats 8 weeks after 5/6 nephrectomy (CRF group) or sham operation (control group).


RESULTS
The CRF group exhibited hypertension, diminished creatinine clearance, increased plasma triglyceride concentration, and elevated total cholesterol-to-HDL cholesterol concentration ratio compared to the corresponding values found in the control group. This was associated with a significant down-regulation of hepatic LRP mRNA expression and immunodetectable LRP protein.


CONCLUSIONS
CRF results in down-regulation of hepatic LRP. This abnormality can, at least in part, account for the previously documented elevation of plasma concentration and depressed clearance of chylomicron remnants and IDL in CRF.
Kim
Choong
C
Division of Nephrology and Hypertension, and Department of Physiology and Biophysics, University of California, Irvine, California, USA.
Vaziri
Nosratola D
ND
D000818:Animals; D002784:Cholesterol / Q000235:genetics; D015536:Down-Regulation; D005786:Gene Expression Regulation; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D026502:LDL-Receptor Related Proteins; D008074:Lipoproteins; C030104:lipoprotein cholesterol; D002784:Cholesterol