A New Low Density Lipoprotein Receptor Related Protein, LRP5, Is Expressed in Hepatocytes and Adrenal Cortex, and Recognizes Apolipoprotein E

Kim, Dong Ho; Inagaki, Yousuke; Suzuki, Takashi; Ioka, Ryoichi X.; Yoshioka, Shiroh Z.; Magoori, Kenta; Kang, Man‐Jong; Cho, Yuko; Nakano, Akira; Liu, Qiong; Fujino, Takahiro; Suzuki, Hiroyuki; Sasano, Hironobu; Yamamoto, Tokuo

doi:10.1093/oxfordjournals.jbchem.a022223

Cited by 112 publications

(90 citation statements)

References 9 publications

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“…In recent years it has become clear that the highly homologous LRP5 LRP6 (Brown et al, 1998) proteins are crucial for reception of the Wnt signal transduction pathway (Pinson et al, 2000;Tamai et al, 2000;Wehrli et al, 2000). Although we lack conclusive evidence regarding the interaction between LRP5/6 and APOE at the cellular and molecular levels, it has been proposed that LRP5/6 may recognize and be involved in APOE catabolism (Kim et al, 1998;Magoori et al, 2003). Moreover, recent experiments suggest that apolipophorins, the ortholog for APOE proteins in Drosophila, copurify and act as vehicles for the movement of lipid-linked morphogens including the Wnt ortholog Wingless (Panakova et al, 2005).…”

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 85%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 85%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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“…Whereas Lrp6 mutants have a reduced number of osteoblasts, Lrp5 primarily regulates the mineralization process. With regard to metabolism, both receptors retain the capacity to bind lipoproteins (71)(72)(73), and, much like LRP5, mutations in LRP6 are associated with metabolic dysfunction in humans (33,74). One potential explanation for the functional difference in osteoblasts may relate to the expression pattern of the coreceptors during osteoblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

125

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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“…In this context, it has been proposed that LRP5/6 may recognize and be involved in APOE catabolism of plasma lipoproteins (65,66). Likewise, it was shown that apolipophorins, the ortholog for APOE proteins in Drosophila, copurify and act as vehicles for the movement of lipid-linked morphogens including the Wnt ortholog Wingless (67).…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

Ferrari

Papassotiropoulos

Biechele

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

258

224

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Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-4 (APOE-4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 3 Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased ␤-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/␤-catenin signaling may be involved in this neurodegenerative disease.neurodegenerative ͉ LRP-6 ͉ single-nucleotide polymorphism ͉ APOE ͉ Wnt

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A New Low Density Lipoprotein Receptor Related Protein, LRP5, Is Expressed in Hepatocytes and Adrenal Cortex, and Recognizes Apolipoprotein E

Cited by 112 publications

References 9 publications

The ups and downs of Wnt signaling in prevalent neurological disorders

The ups and downs of Wnt signaling in prevalent neurological disorders

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

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