Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor.
Key result
In mice lacking the LDL receptor, the initial hepatic removal of chylomicron remnants is unaffected, but their subsequent endocytosis is dramatically reduced and proceeds via a slower, RAP-sensitive process.
Population
Normal mice and LDLR-deficient [LDLR (-/-)] mice
Comparison
Intravenous injection of chylomicrons, with or… vs Normal mice vs LDLR mice; with vs without RAP…
Design
Preclinical
Follow-up
Up to 30 minutes and after 30 minutes post-injection
Authors
Discussion
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Implication
Suggests LDLR-independent initial remnant clearance in mice; leaves open human relevance and therapeutic targeting.
Structured PICO
P
Population
Normal and LDLR-deficient mice used to evaluate the role of LDLR and LRP in the hepatic metabolism of chylomicron remnants.
I
Intervention
Intravenous injection of chylomicrons, with or without receptor-associated protein (RAP)
C
Comparator
Normal mice vs LDLR (-/-) mice; with vs without RAP coadministration
O
Outcome
Hepatic removal and endocytosis of chylomicron remnants (measured by accumulation in the endosomal fraction and rate of hydrolysis of component cholesteryl esters)surrogate
Main Result
Absolute Event Rate: 0.52% vs 4.9%
p-value: p=<0.01
Initial hepatic removal of chylomicron remnants is primarily mediated by mechanisms independent of LDLR or LRP, while subsequent endocytosis is predominantly mediated by LDLR.
Limitations
- Estimates of the rate of hydrolysis could be imprecise due to exchange of unesterified cholesterol with cell membranes and potential reentry into blood or bile.
Cite This Study
Herz et al. (1995) studied Low density lipoprotein receptor (LDLR) deficiency. LDLR deficiency and RAP administration vs. Normal mice / GST administration was evaluated on Recovery of chylomicron cholesteryl esters in hepatic endosomes 20 minutes after injection (% of in liver) (p=<0.01). In mice lacking the LDL receptor, the initial hepatic removal of chylomicron remnants is unaffected, but their subsequent endocytosis is dramatically reduced and proceeds via a slower, RAP-sensitive process.