Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

Abstract

The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1 Low density lipoprotein receptor-related protein-1 (LRP1), 2 the largest member of the low density lipoprotein (LDL) receptor gene family, is composed of an extracellular 515-kDa polypeptide covalently linked to an 85-kDa polypeptide that spans the plasma membrane and extrudes into the cytosol (1). The extracellular domain of LRP1 includes 31 cysteine-rich complement-like repeats responsible for ligand binding and 22 cysteine-rich repeats that are homologous to the ␤-propeller domains in the epidermal growth factor precursor protein (1).Structural similarities between these cysteine-rich repeats of LRP1 and the ligand-binding domain of the LDL receptor have led to its identification as the chylomicron remnant receptor responsible for hepatic clearance of apolipoprotein E (apoE)-containing lipoproteins (2-5). Subsequent studies revealed that LRP1 is also capable of binding and mediating cellular uptake of other ligands, including activated ␣ 2 -macroglobulin, proteaseprotease inhibitor complexes, and lysosomal hydrolases such as the saposin precursor protein prosaposin (6, 7). Additionally, recent evidence also established LRP1 as an integrator of signal transduction events in cell regulation, including the modulation of PDGF receptor and TGF␤-1 receptor activation (8 -10), Wnt signaling (11), and participation in neurotransmitter-dependent postsynaptic responses (12). The function of LRP1 as a cargo transporting endocytic receptor or a cell signaling receptor appears to be tissue-and cell type-specific (13). For example, LRP1 serves as a signaling receptor during adipocyte differentiation via activation of Wnt5a/␤-catenin pathway and inhibition of acetyl-CoA carboxylase phosphorylation (11). In contrast, LRP1 is a cargo transporting receptor in mature adipocytes responsible for the uptake of lipid nutrients from triglyceride-rich lipoproteins for storage and utilization (14). The function of LRP1 in smooth muscle cells is also unrelated to cargo transport, but its modulation of PDGF receptor and TGF␤-1 receptor activities is essential for maintenance of vascular reactivity and limiting hypercholesterolemia-induced atherosclerosis and injury-induced neointimal hyperplasia (8 -10). In the neurons of dendritic synapses, LRP1 interacts with the N-methyl-D-aspartate receptor to modulate neuronal calcium signaling (15). Neuronal expression of LRP1 also activates protein kinase B/Akt signaling in protection against stress-induced apoptosis (16). In addition, LRP1 has been shown to participate in focal adhesion and cell migration via direct association with integrins and/or modulation of calreticu...

Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia

“…However, because other mechanisms that are associated with the change in serum triglyceride level have been illustrated in diabetes (Bell et al 2011) and thiazolidinedione treatment (Hanefeld 2009), our in vivo data cannot conclude a causal relationship between hepatic LRP1 expression and serum triglyceride level. In addition, previous studies reported that hepatic LRP1 deficiency did not influence serum triglyceride level (Rohlmann et al 1998, Basford et al 2011. In this study, we used OLETF rats fed a high-fat diet as a diabetic animal model whereas previous studies used mice fed a normal chow diet.…”

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…LRP1 is also critical for lipid transport and metabolism in adipocytes (12,41,42). It improves the hepatic HDL/ LDL secretion ratio (43) and protects hepatocytes from lipotoxic insults (44). Based on these reports in the literature, LRP1 clearly performs unique functions in a cell type-specific way.…”

LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes

“…Animals and Tissue Analysis-Liver-specific LRP1-null (hLrp1 cre recombinase transgenic mice in C57BL/6 background (Jackson Laboratory, Bar Harbor, ME) as described previously (13). The animals were maintained under controlled environmental conditions with free access to food and water.…”

“…Thus, LRP1 has dual signal transduction and cargo endocytosis functions in adipocyte biology. In hepatocytes, in addition to chylomicron remnants and protease complex clearance, LRP1 is also required to complement the mannose 6-phosphate receptor for appropriate lysosomal enzyme trafficking, and its defect impairs prosaposin activation, leading to reduced ABCA1 cell surface translocation and lower HDL secretion (13).…”