Low-density lipoprotein receptor-related protein 2(LRP2)is required for lipid export in the midgut of the migratory locust,Locusta migratoria

Low-density lipoprotein receptor-related protein 2(LRP2)is a multifunctional endocytic receptor expressed in epithelial cells.In mammals,it acts as an endocytic receptor that mediates the cellular uptake of cholesterol-containing apolipoproteins to maintain lipid homeostasis.However,little is known about the role of LRP2 in lipid homeostasis in insects.In the present study,we investigated the function of LRP2 in the migratory locust Locusta migratoria(LmLRP2).The mRNA of LmLRP2 is widely distributed in various tissues,including integument,wing pads,foregut,midgut,hindgut,Malpighian tubules and fat body,and the amounts of LmLRP2 transcripts decreased gradually in the early stages and then increased in the late stages before ecdysis during the nymphal developmental stage.Fluorescence immunohistochemistry revealed that the LmLRP2 protein is mainly located in cellular membranes of the midgut and hindgut.Using RNAi to silence LmLRP2 caused molting defects in nymphs(more than 60%),and the neutral lipid was found to accumulate in the midgut and surface of the integument,but not in the fat body,of dsLmLRP2-treated nymphs.The results of a lipidomics analysis showed that the main components of lipids(diglyceride and triglyceride)were significantly increased in the midgut,but decreased in the fat body and hemolymph.Furthermore,the content of total triglyceride was significantly increased in the midgut,but markedly decreased in the fat body and hemolymph in dsLmLRP2-injected nymphs.Our results indicate that LmLRP2 is located in the cellular membranes of midgut cells,and is required for lipid export from the midgut to the hemolymphand fat body in locusts.

Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect

Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.

Association between Low-density Lipoprotein Receptor-related Protein 5 Polymorphisms and Type 2 Diabetes Mellitus in Han Chinese:a Case-control Study

Objective To investigate the association between low-density lipoprotein receptor-related protein 5 （LRPS） variants （rs12363572 and rs4930588） and type 2 diabetes mellitus （T2DM） in Han Chinese. Methods A total of 1842 T2DM cases （507 newly diagnosed cases and 1335 previously diagnosed cases） and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms （SNPs）. Odds ratios （ORs） and 95% confidence intervals （95% CIs） were calculated to describe the strength of the association by logistic regression. Results In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index （BMI）, the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype ~ was associated with reduced risk of T2DM （OR 0.820, 95% CI 0.732-0.919）. In addition, rs12363572 was associated with BMI （P〈0.001） and rs4930588 was associated with triglyceride levels （P=0.043） in 507 newly diagnosed T2DM cases but not in healthy controls. Conclusion No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM.

Low-density lipoprotein receptor-related protein 1 is a CROPs-associated receptor for Clostridioides infection toxin B

As the leading cause of worldwide hospital-acquired infection,Clostridioides difficile(C.difficile)infection has caused heavy economic and hospitalized burden,while its pathogenesis is not fully understood.Toxin B(Tcd B)is one of the major virulent factors of C.difficile.Recently,CSPG4 and FZD2 were reported to be the receptors that mediate Tcd B cellular entry.However,genetic ablation of genes encoding these receptors failed to completely block Tcd B entry,implicating the existence of alternative receptor(s)for this toxin.Here,by employing the CRISPR-Cas9 screen in CSPG4-deficient He La cells,we identified LDL receptor-related protein-1(LRP1)as a novel receptor for Tcd B.Knockout of LRP1 in both CSPG4-deficient He La cells and colonic epithelium Caco2 cells conferred cells with increased Tcd B resistance,while LRP1 overexpression sensitized cells to Tcd B at a low concentration.Co-immunoprecipitation assay showed that LRP1 interacts with full-length Tcd B.Moreover,CROPs domain,which is dispensable for Tcd B’s interaction with CSPG4 and FZD2,is sufficient for binding to LRP1.As such,our study provided evidence for a novel mechanism of Tcd B entry and suggested potential therapeutic targets for treating C.difficile infection.

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR

Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.

Wnt signaling control of bone cell apoptosis

Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.

Roles of low?density lipoproteinreceptor?related protein 1 in tumors

Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer's disease

Current evidence shows that apolipoprotein E （APOE）, apolipoprotein CI （APOC1） and low density lipoprotein receptor-related protein （LRP） variations are related to late-onset Alzheimer＇s disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer＇s disease patients. We performed a 30-month longitudi- nal cohort study to investigate the relationship between Alzheimer＇s disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer＇s disease were recruit- ed form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess pa- tients＇ cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE 4 carriers compared with non-carriers. In addition, the APOE 4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive im- pairment progression group. In conclusion, APOE e4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ~4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer＇s disease.

The uPA/uPAR system in astrocytic wound healing

The repair of injured tissue is a highly complex process that involves cell prolife ration,differentiation,and migration.Cell migration requires the dismantling of intercellular contacts in the injured zone and their subsequent reconstitution in the wounded area.Urokinase-type plasminogen activator(u PA)is a serine proteinase found in multiple cell types including endothelial cells,smooth muscle cells,monocytes,and macrophages.A substantial body of experimental evidence with different cell types outside the central nervous system indicates that the binding of uPA to its receptor(uPAR)on the cell surface prompts cell migration by inducing plasmin-mediated degradation of the extracellular matrix.In contrast,although uPA and uPAR are abundantly found in astrocytes and u PA binding to uPAR triggers astrocytic activation,it is unknown if uPA also plays a role in astrocytic migration.Neuronal cadherin is a member of cell adhesion proteins pivotal for the formation of cell-cell conta cts between astrocytes.More specifically,while the extracellular domain of neuronal cadherin interacts with the extracellular domain of neuronal cadherin in neighboring cells,its intracellular domain binds toβ-catenin,which in turn links the complex to the actin cytos keleton.Glycogen synthase kinase 3βis a serine-threonine kinase that prevents the cytoplasmic accumulation ofβ-catenin by inducing its phosphorylation at Ser33,Ser37,and Ser41,thus activating a sequence of events that lead to its proteasomal degradation.The data discussed in this perspective indicate that astrocytes release u PA following a mechanical injury,and that binding of this u PA to uPAR on the cell membrane induces the detachment ofβ-catenin from the intracellular domain of neuronal cadherin by triggering its extracellular signal-regulated kinase 1/2-mediated phosphorylation at Tyr650.Remarkably,this is followed by the cytoplasmic accumulation ofβ-catenin because uPA-induced extracellular signalregulated kinase 1/2 activation also phosphorylates lipoprotein receptor-related protein 6 at Ser1490,which in turn,by recruiting glycogen synthase kinase 3βto its intracellular domain abrogates its effect onβ-catenin.The cytoplasmic accumulation ofβ-catenin is followed by its nuclear translocation,where it induces the expression of uPAR,which is required for the migration of astrocytes from the injured edge into the wounded area.

Lack of Association of Common Polymorphism of LRP1 Gene with Myocardial Infarction in a Chinese Han Population

This study examined the association of a common polymorphic allele（25G） of the low-density lipoprotein receptor-related protein1（LRP1） gene with myocardial infarction（MI）.The genotypes of LRP1 25CG（rs35282763） were determined in 347 MI patients and 347 age-and sex-frequency-matched controls from an unrelated Chinese Han population.Factor Ⅷ（FⅧ） levels were measured in the MI patients and controls by chromogenic assay and enzyme-linked immunosor-bent assay（ELISA）.The results showed that LRP1 25CG（rs35282763） genotype distribution did not differ significantly between patients（n=206 for 25CC,n=122 for 25CG） and controls（n=191 for 25CC,n=126 for 25CG;P0.05）.The 25G allele was not associated with a reduced risk of MI（P0.05）.Further stratifications for age,sex,and other cardiovascular risk factors did not affect the negative findings.It was concluded that the presence of the G allele at the 25CG（rs35282763） polymorphism of the LRP1 is not associated with a reduced risk of MI,and genotyping for LRP1 25CG（rs35282763） polymor-phism is not useful in assessing the individual risk of MI.

Perfluorinated iodine alkanes promote the differentiation of mouse embryonic stem cells by regulating estrogen receptor signaling

Investigating the development toxicity of perfuorinated iodine alkanes(PFIs)is critical,given their estrogenic effects through binding with estrogen receptors(ERs).In the present study,two PFIs,including dodecafuoro-1,6-diiodohexane(PFHx DI)and tridecafuorohexyl iodide(PFHx I),with binding preference to ERαand ERβ,respectively,were selected to evaluate their effects on proliferation and differentiation of the mouse embryonic stem cells(m ESCs).The results revealed that,similar to E_(2),50μmol/L PFHx DI accelerated the cell proliferation of the m ESCs.The PFI stimulation at the exposure concentrations of 2–50μmol/L promoted the differentiation of the m ESCs as characterized by the upregulation of differentiation-related biomarkers(i.e.,Otx2 and Dnmt3β)and downregulation of pluripotency genes(i.e.,Oct4,Nanog,Sox2,Prdm14 and Rex1).Comparatively,PFHx DI exhibited higher induction effect on the differentiation of the m ESCs than did PFHx I.The tests on ER signaling indicated that both PFI compounds induced exposure concentration-dependent expressions of ER signaling-related biomarkers(i.e.,ERα,ERβand Caveolin-1)in the m ESCs,and the downstream ER responsive genes(i.e.,c-fos,c-myc and c-jun)well responded to PFHx I stimulation.The role of ER in PFI-induced effects on the m ESCs was further validated by the antagonistic experiments using an ER inhibitor(ICI).The findings demonstrated that PFIs triggered ER signaling,and perturbed the differentiation program of the m ESCs,causing the potential health risk during early stage of development.