Distribution of the lipolysis stimulated receptor in adult and embryonic murine tissues and lethality of LSR–/– embryos at 12.5 to 14.5 days of gestation

Mesli, Samir; Javorschi, Sandrine; Bérard, Annie M.; Landry, Marc; Priddle, Helen; Kivlichan, David; Smith, Andrew J.H.; Yen, Frances T.; Bihain, Bernard E.; Darmon, Michel

doi:10.1111/j.1432-1033.2004.04223.x

Cited by 66 publications

(66 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inactivation of the LSR gene leads to embryonic lethality in homozygous mice (25). In this study we show delayed postprandial lipid clearance in mice with a single functional LSR allele (LSR Ϫ/ϩ ) and demonstrate in vivo the role of the LSR gene product in the clearance of both TG-rich particles and LDL.…”

Section: Triglyceride (Tg)mentioning

confidence: 79%

“…Animals and Diet-LSR heterozygote mice on a C57Bl/6J background after Ͼ4 generations (25) were transferred from Bordeaux and re-derivatized into the same strain C57Bl/6J mice (Janvier Breeding) before being introduced into a specific pathogen-free, certified animal facility authorized to house transgenic animals. For these studies, LSR Ϫ/ϩ male mice were used with LSR ϩ/ϩ littermates.…”

Section: Methodsmentioning

confidence: 99%

“…PCR conditions and primers for wild-type LSR were used as previously described (25). For the transgene, oligos used were forward primer, 5Ј-GCTTTTCTGGATTCATCGACTGT-3Ј, and reverse primer, 5Ј-TTACCCATTTTCTTATCCTCTCT-TCC-3Ј, corresponding to intron 5 of LSR gene and the neomycin cassette, respectively.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Lipolysis Stimulated Lipoprotein Receptor

Yen

Roitel²,

Bonnard³

et al. 2008

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The lipolysis-stimulated lipoprotein receptor, LSR, is a multimeric protein complex in the liver that undergoes conformational changes upon binding of free fatty acids, thereby revealing a binding site(s) that recognizes both apoB and apoE. Complete inactivation of the LSR gene is embryonic lethal in mice. Here we show that removal of a single LSR allele (LSR ؊/؉ ) caused statistically significant increases in both plasma triglyceride and cholesterol levels, a 2-fold increase in plasma triglyceride changes during the post-prandial phase, and delayed clearance of lipid emulsions or a high fat meal. The longer postprandial lipoprotein clearance time observed in LSR ؊/؉ mice was further increased in LSR ؊/؉ mice lacking functional low density lipoprotein (LDL) receptors. LSR ؊/؉ mice placed on a Westerntype diet displayed higher plasma triglycerides and cholesterol levels, increased triglyceride-rich lipoproteins and LDL, and increased aorta lipid content, as compared with control mice on the same diet. Furthermore, a direct correlation was observed between the hyperlipidemia and weight gain but only in the LSR ؊/؉ mice. Knockdown of LSR expression by small interfering RNA in mouse Hepa1-6 cells led to decreased internalization of both DiI-labeled cyclohexanedione-LDL and very low density lipoprotein in the presence of oleate. These data led us to conclude that LSR contributes to the physiological clearance of atherogenic triglyceride-rich lipoproteins and LDL. We propose that LSR cooperates with the LDL receptor in the final hepatic processing of apoB-containing lipoproteins and represents a novel therapeutic target for the treatment of hyperlipidemia associated with obesity and atherosclerosis. Triglyceride (TG)2 -rich apoB-containing lipoproteins are produced by the liver as VLDL or by the intestine as chylomicrons (1). Both types of particles deliver their TG load to peripheral tissues through interactions with lipoprotein lipase (LpL) anchored to capillary endothelium heparan sulfate proteoglycans (HSPGs) (1). The residual cholesterol enriched inter-mediate density lipoprotein (IDL) and LDL for VLDL, and chylomicrons remnants are then removed from the circulation by hepatocytes. Clearance of these lipoproteins in the liver is a complex process through which the particles enter the space of Disse, bind to HSPGs, acquire apoE, and interact with hepatic lipase and LpL (2). After this, the residual particles are delivered to endocytic receptors for cellular internalization and degradation (3).The LDL receptor (LDL-R) accounts for most of LDL removal and contributes to part of the uptake of chylomicron remnants (4, 5). This highly informative endocytic receptor prototype nevertheless leaves two unsolved issues regarding apoB-containing lipoprotein clearance. First, in the absence of functional LDL-R, the amount of LDL cleared daily is 2-fold greater than that of subjects with normal LDL-R activity (6) and has been shown to take place in the liver (7). Second, the clearance of intestinally derived chylomicron remnan...

show abstract

Section: Triglyceride (Tg)mentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Lipolysis Stimulated Lipoprotein Receptor

Yen

Roitel²,

Bonnard³

et al. 2008

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although a total of 23 redundant phosphopeptides were detected for LSR (SI Table 2), all 12 nonredundant sites were contained within this set of six phosphopeptides. LSR is thought to be involved in the clearance of triglyceride-rich lipoproteins (29), and the expression of LSR is critical for liver and embryonic development (30). LSR was highly phosphorylated and contained sites primarily suggestive of basophilic kinases (Rxxs) but also had acidiphilic (sxxE) and Pro-directed (sP) phosphorylation.…”

mentioning

confidence: 99%

Large-scale phosphorylation analysis of mouse liver

Villén

Beausoleil

Gerber

et al. 2007

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

692

775

View full text Add to dashboard Cite

Protein phosphorylation is a complex network of signaling and regulatory events that affects virtually every cellular process. Our understanding of the nature of this network as a whole remains limited, largely because of an array of technical challenges in the isolation and high-throughput sequencing of phosphorylated species. In the present work, we demonstrate that a combination of tandem phosphopeptide enrichment methods, high performance MS, and optimized database search/data filtering strategies is a powerful tool for surveying the phosphoproteome. Using our integrated analytical platform, we report the identification of 5,635 nonredundant phosphorylation sites from 2,328 proteins from mouse liver. From this list of sites, we extracted both novel and known motifs for specific Ser/Thr kinases including a ''dipolar'' motif. We also found that C-terminal phosphorylation was more frequent than at any other location and that the distribution of potential kinases for these sites was unique. Finally, we identified double phosphorylation motifs that may be involved in ordered phosphorylation.mass spectrometry ͉ proteomics I n eukaryotes, protein phosphorylation is among the most important regulatory events in cells, guiding primary biological processes, such as cell division, growth, migration, differentiation, and intercellular communication (1, 2). Numerous efforts to study protein phosphorylation continue to provide the scientific community with an expanding phosphorylation database resource. Sequence alignment studies (3) have defined which genes encode protein kinases. In addition, in vitro reactions of kinases with synthetic peptide libraries have been used to define kinase specificities (4, 5). Finally, protein targets for individual kinases are being defined through elegant systematic studies (6-8). Notwithstanding, only MS-based proteomics currently provides the capability to identify at once and on a massive scale kinase substrates and the specific positions of their modification (9).A major goal of systems biology is to integrate all in vivo phosphorylation events into the context of an organism. Phosphorylation analysis from primary tissue, in contrast to immortalized cell lines, best represents events that are occurring in the basal physiological state of an organism even though tissues often contain heterogeneous populations of cells. In the present study we chose mouse liver as a model tissue for establishing a pipeline for large-scale phosphorylation analysis. In addition, protein phosphorylation plays a critical role in normal liver development and function; therefore, the sites obtained here could be further characterized into physiological context. Several phosphorylation-related (PI3K and Akt signaling) liver phenotypes have been reported to be related to altered lipid and glucose metabolism via insulin control (10, 11) and liver regeneration (ribosomal protein S6) (12). Previously, only two studies have examined phosphorylation sites from liver tissue with 26 (13) and 339 (14) sites.As the fie...

show abstract

“…The lsr gene was inactivated in 129/Ola ES cells by the deletion of a gene segment containing exons 2-5, and then injected into mouse embryos. Complete suppression of this gene proved to be lethal at the embryonic stage (Mesli et al, 2004). Even though 3 LSR -/-males were produced in the initial reproduction, they proved to be weak and sterile.…”

Section: In Vivo Studiesmentioning

confidence: 99%