Development and Analysis of an Animal Model of Autosomal Recessive Hypercholesterolemia



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The low density lipoprotein receptor (LDLR) in the liver is the major route of removal of LDL cholesterol (LDL-C) from the blood. Defects in LDLR cause familial hypercholesterolemia (FH), which is characterized by elevated LDL-C, premature coronary atherosclerosis, and autosomal dominant inheritance. A similar clinical picture with an autosomal recessive mode of inheritance occurs in autosomal recessive hypercholesterolemia (ARH). ARH is caused by mutations in the ARH gene, which encodes for a putative adaptor protein implicated in linking the LDLR to the endocytic machinery. To determine the role of ARH in LDLR function, mice that do not express ARH were developed via targeted gene disruption. Similarly to ARH patients, Arh + mice have fractional catabolic rates (FCRs) for LDL similar Ldlr + mice, yet have much less severe elevations in LDL-C when fed normal chow. Upon cholesterol feeding, however, plasma lipoprotein profiles between Ldlr + and Arh + were indistinguishable. Immunolocalization studies reveal normal sorting but defective internalization of LDLRs in the livers of Arh + mice. Whereas the clearance of LDL was markedly and similarly delayed in the Arh+ and Ldlr+ mice, the rate of removal of VLDL was significantly higher in Arh + mice compared to Ldlr + animals. Primary hepatocytes expressing human LDLRs rapidly accumulated fluorescently labeled !-VLDL, but failed to internalize labeled LDL, monoclonal anti-LDLR antibody, or antibody:Protein A tetramers in the absence of ARH. These findings indicate ARH is caused by delayed clearance of LDL by LDLRs in the liver, but the severity of the disease is ameliorated by preserved VLDL clearance in the absence ARH. Thus the lower levels of LDL-C in ARH compared to FH are due to reduced production of LDL from VLDL.

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