scholarly journals Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor

2002 ◽  
Vol 157 (2) ◽  
pp. 303-314 ◽  
Author(s):  
Masaki Kato ◽  
Millan S. Patel ◽  
Regis Levasseur ◽  
Ivan Lobov ◽  
Benny H.-J. Chang ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Osteoblast Proliferation ◽  
Targeted Disruption ◽  
Independent Manner ◽  
Wnt Proteins ◽  
Density Lipoprotein Receptor ◽  
And Function

The low-density lipoprotein receptor–related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

scholarly journals Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jinuk Kim ◽  
Wonhee Han ◽  
Taeyong Park ◽  
Eun Jin Kim ◽  
Injin Bang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Low Density Lipoprotein ◽  
Wnt Signaling Pathway ◽  
Density Lipoprotein ◽  
Interaction Sites ◽  
Wnt Proteins ◽  
C Terminus ◽  
Density Lipoprotein Receptor

Abstract Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2–SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.

scholarly journals A novel peroxisome proliferator response element modulates hepatic low-density lipoprotein receptor gene transcription in response to PPARδ activation

2015 ◽  
Vol 472 (3) ◽  
pp. 275-286 ◽  
Author(s):  
Vikram R. Shende ◽  
Amar Bahadur Singh ◽  
Jingwen Liu
Keyword(s):  
Gene Transcription ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Density Lipoprotein Receptor ◽  
Peroxisome Proliferator Response Element

PPARδ activation beneficially regulates lipid metabolism. We have now identified a novel function of PPARδ that increases LDL receptor gene transcription in hepatic cells in vitro and in vivo through direct binding to a PPRE motif on LDLR promoter.

scholarly journals Low-Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity

2018 ◽  
Author(s):  
Wei-Chun Chang ◽  
Hsiao-Ching Wang ◽  
Wei-Chung Cheng ◽  
Juan-Cheng Yang ◽  
Wei-Min Chung ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Bioinformatics Analyses ◽  
Density Lipoprotein Receptor ◽  
Cisplatin Sensitivity

Platinum-based therapy remains the cornerstone for cancer patient management; however, its efficacy varies. This study demonstrated the differential expressions of low-density lipoprotein receptor (LDLR) in subtypes of epithelial ovarian carcinoma (EOC) determines cisplatin sensitivity. It's sensitive in serous EOCs (low LDLR), where insensitive in endometrioid and clear cell EOCs (high LDLR). Meanwhile, knocked-down or overexpressed LDLR in EOC could reversed the chemosensitivity pattern both in vitro and in vivo. Mechanistic dissection with transcriptome vs. lipidome trans-omics analyses elucidated the LDLR-->LPC (Lyso-PhosphotidylCholine)-->FAM83B (phospholipase-related)-->FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis in cisplatin insensitivity. Implementing LPC-liposome encapsulated cisplatin could facilitate DNA-adduct formation via lipid droplets (LDs) delivery. Furthermore, Bioinformatics analyses found that the LDL/R-->LD homeostasis alteration is critical for therapeutic prognosis. Lastly, using LPC-liposome-cisplatin improved cisplatin sensitivities in gastric cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma cells. In conclusion, this report discovered a LDL/R-reprogrammed transcriptome-lipidome network, by which impulses platinum insensitivity and disease outcome. The drug specific lipidome for liposome manufacture might be an efficienct pharmaceutics strategy for chemoagents.

scholarly journals Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Rui Sun ◽  
Mengna Peng ◽  
Pengfei Xu ◽  
Feihong Huang ◽  
Yi Xie ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Neurological Deficits ◽  
Density Lipoprotein Receptor ◽  
Cerebral Ischemic

Abstract Background Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated. Methods Ischemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice. Results The expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1β and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr−/− mice and cultured Ldlr−/− neuron after experimental stroke. Conclusions These results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.

scholarly journals Peroxisome proliferator-activated receptor-γ regulates the expression and function of very-low-density lipoprotein receptor

2010 ◽  
Vol 298 (1) ◽  
pp. E68-E79 ◽  
Author(s):  
Huan Tao ◽  
Srikanth Aakula ◽  
Naji N. Abumrad ◽  
Tahar Hajri
Keyword(s):  
Adipose Tissue ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
And Function

Very-low-density lipoprotein receptor (VLDLR) is a member of the low-density receptor family, highly expressed in adipose tissue, heart, and skeletal muscle. It binds apolipoprotein E-triglyceride-rich lipoproteins and plays a significant role in triglyceride metabolism. PPARγ is a primary regulator of lipid metabolism in adipocytes and controls the expression of an array of genes involved in lipid trafficking in adipocytes. However, it is not known whether VLDLR is also under the control of PPARγ. In this study, we investigated the role of PPARγ in the regulation of VLDLR expression and function in vivo and in vitro. During the differentiation of 3T3-L1 preadipocytes, the levels of VLDLR protein and mRNA increased in parallel with the induction of PPARγ expression and reached maximum in mature adipocytes. Treatment of differentiated adipocytes with PPARγ agonist pioglitazone upregulated VLDLR expression in dose- and time-dependent manners. In contrast, specific inhibition of PPARγ significantly downregulated the protein level of VLDLR. Induction of VLDLR is also demonstrated in vivo in adipose tissue of wild-type (WT) mice treated with pioglitazone. In addition, pioglitazone increased plasma triglyceride-rich lipoprotein clearance and increased epididymal fat mass in WT mice but failed to induce similar effects in vldlr−/−mice. These results were further corroborated by the finding that pioglitazone treatment enhanced adipogenesis and lipid deposition in preadipocytes of WT mice, while its effect in VLDLR-null preadipocytes was significantly blunted. These findings provide direct evidence that VLDLR expression is regulated by PPARγ and contributes in lipid uptake and adipogenesis.

scholarly journals Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis

2019 ◽  
Vol 216 (2) ◽  
pp. 350-368 ◽  
Author(s):  
Ludwig T. Weckbach ◽  
Ulrich Grabmaier ◽  
Andreas Uhl ◽  
Sebastian Gess ◽  
Felicitas Boehm ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Systolic Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Polymorphonuclear Neutrophils ◽  
Autoimmune Myocarditis ◽  
Cardiac Inflammation ◽  
Density Lipoprotein Receptor

Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor–related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation.

scholarly journals Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion

2021 ◽  
Author(s):  
Maximillian A Rogers ◽  
Joshua D Hutcheson ◽  
Takehito Okui ◽  
Claudia Goettsch ◽  
Sasha A Singh ◽  
...  
Keyword(s):  
Disease Risk ◽  
Mitochondrial Fission ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mrna Levels ◽  
Related Protein ◽  
Pcsk9 Inhibitor ◽  
Density Lipoprotein Receptor

Abstract Aims Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release and incorporation of trafficking vesicles mediates protein secretion and degradation. We hypothesized that ER remodeling that drives mitochondrial fission participates in cardiometabolic proteostasis. Methods and results We used in vitro and in vivo hepatocyte inhibition of a protein involved in mitochondrial fission, dynamin-related protein 1 (DRP1). Here, we show that DRP1 promotes remodeling of select ER microdomains by tethering vesicles at ER. A DRP1 inhibitor, mitochondrial division inhibitor 1 (mdivi-1) reduced ER localization of a DRP1 receptor, mitochondrial fission factor, suppressing ER remodeling-driven mitochondrial fission, autophagy, and increased mitochondrial calcium buffering and PCSK9 proteasomal degradation. DRP1 inhibition by CRISPR/Cas9 deletion or mdivi-1 alone or in combination with statin incubation in human hepatocytes and hepatocyte-specific Drp1-deficiency in mice reduced PCSK9 secretion (−78.5%). In HepG2 cells, mdivi-1 increased low-density lipoprotein receptor via c-Jun transcription and reduced PCSK9 mRNA levels via suppressed sterol regulatory binding protein-1c. Additionally, mdivi-1 reduced macrophage burden, oxidative stress, and advanced calcified atherosclerotic plaque in aortic roots of diabetic Apoe-deficient mice and inflammatory cytokine production in human macrophages. Conclusions We propose a novel tethering function of DRP1 beyond its established fission function, with DRP1-mediated ER remodeling likely contributing to ER constriction of mitochondria that drives mitochondrial fission. We report that DRP1-driven remodeling of select ER micro-domains may critically regulate hepatic proteostasis and identify mdivi-1 as a novel small molecule PCSK9 inhibitor.

scholarly journals Neurotoxic astrocytes secreted glypican-4 drives Alzheimer’s tau pathology

2020 ◽  
Author(s):  
Ana Pereira ◽  
Sivaprakasam Ramamoorthy
Keyword(s):  
Late Onset ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tau Pathology ◽  
Unfolded Protein ◽  
Density Lipoprotein Receptor ◽  
Protein Response ◽  
Lipoprotein Receptor Related Protein

Abstract Apolipoprotein E4 (APOE4) is the most crucial genetic risk factor of late-onset Alzheimer’s disease (AD). However, the mechanism through which APOE4 induces AD risk remains unknown. Here, we report the astrocyte-secreted protein glypican-4 (GPC-4), as a novel binding partner of APOE4, drives tau pathology. APOE4-carrying AD patients display more tau accumulation compared to APOE4-noncarring AD patients. GPC-4 is highly expressed in APOE4 AD patients, and is regulated by microglial factors via NF-κB signaling pathway. The astrocyte-secreted GPC-4 induced both tau accumulation and spreading in vitro and in vivo. Further, GPC-4 is required for APOE4-mediated surface trafficking of low-density lipoprotein receptor-related protein 1 (LRP1) and tau propagation. GPC-4 activates unfolded protein response (UPR) pathway IRE1α, and pharmacological inhibition of IRE1α with KIRA6 blocks GPC-4 induced tau propagation. Together, our data comprehensively demonstrate that the APOE4-induced AD risk is directly mediated by GPC-4, and that perturbing GPC-4 induced IRE1α pathway has therapeutic opportunities.

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