Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia
Christopher Jones, … , Joachim Herz, Helen H. Hobbs
Christopher Jones, … , Joachim Herz, Helen H. Hobbs
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):165-174. https://doi.org/10.1172/JCI29415.
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Research Article

Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

Abstract

Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr–/–) and ARH (Arh–/–). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh–/– mice compared with Ldlr–/– mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh–/– mice than in Ldlr–/– mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh–/– mice (but not Ldlr–/– mice) internalized β-migrating VLDL (β-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH.

Authors

Christopher Jones, Rita Garuti, Peter Michaely, Wei-Ping Li, Nobuyo Maeda, Jonathan C. Cohen, Joachim Herz, Helen H. Hobbs

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Figure 2

VLDL production rates of Arh–/–, Ldlr–/–, and wild-type mice on normal chow and high-sucrose diets.

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VLDL production rates of Arh–/–, Ldlr–/–, and wild-type mice on normal c...
(A) Male Arh–/– (diamonds), Ldlr–/– (circles), and wild-type (squares) mice (14–16 weeks of age) were injected with 300 mg/kg Triton WR-1339 (15% w/v in 0.9% NaCl). Prior to injection, the mice were maintained on a normal chow diet (left) or a high-sucrose diet (right) for 6 weeks. Blood was sampled from the retro-orbital plexus after a 6-hour fast at the time points indicated, and the triglycerides were measured enzymatically as described in Methods. VLDL production rates were calculated from the slope of a line determined using least squares regression. (B) apoB production in Arh–/–, Ldlr–/–, and wild-type mice. Male Arh–/– (diamonds), Ldlr–/– (circles), and wild-type (squares) mice (n = 4), 18–22 weeks of age, on a chow diet were injected with 300 mg/kg Triton WR-1339 (15% w/v in 0.9% NaCl) after a 6-hour fast. Blood was sampled from the retro-orbital plexus at the times indicated. Plasma aliquots from individual mice were pooled, and VLDL was separated as described in Methods. The resulting apolipoproteins were separated by SDS-PAGE and stained with colloidal Coomassie blue. Scanning densitometry was used to determine the relative amounts of apoB48 and apoB100 in each sample.