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J Herz

Publications and source records attributed to J Herz.

At least 19 recordsLinked to original sources
PubMed2007

Conditional animal models for the study of lipid metabolism and lipid disorders.

The advent of technologies that allow conditional mutagenesis has revolutionized our ability to explore gene functions and to establish animal models of human diseases. Both aspects have proven to be of particular importance in the study of lipid-related disorders. Classical approaches to gene inactivation by conventional gene targeting strategies have been successfully applied to generate animal models like the LDL receptor- and the apolipoprotein E-knockout mice, which are still widely used to study diverse aspects of atherosclerosis, lipid transport, and neurodegenerative disease. In many cases, however, simply inactivating the gene of interest has resulted in early lethal or complex phenotypes which are difficult to interpret. In recent years, additional tools have therefore been developed that allow the spatiotemporally controlled manipulation of the genome, as described in detail in Part I of this volume. Our aim is to provide an exemplary survey of the application of different conditional mutagenesis techniques in lipid research in order to illustrate their potential to unravel physiological functions of a broad range of genes involved in lipid homeostasis.

Animals↗
PubMed2006

Macrophage low-density lipoprotein receptor-related protein deficiency enhances atherosclerosis in ApoE/LDLR double knockout mice.

OBJECTIVE: In vitro studies implicate that the low-density lipoprotein receptor (LDLR)-related protein (LRP) in macrophages has a pro-atherogenic potential. In the present study, we investigated the in vivo role of macrophage specific LRP in atherogenesis independent of its role in the uptake of lipoproteins. METHODS AND RESULTS: We generated macrophage-specific LRP-deficient mice on an apoE/LDLR double-deficient background. Macrophage LRP deletion did not affect plasma cholesterol and triglyceride levels, lipoprotein distribution, and blood monocyte counts. Nevertheless, macrophage LRP deficiency resulted in a 1.8-fold increase in total atherosclerotic lesion area in the aortic root of 18-week-old mice. Moreover, LRP deficiency also resulted in a relatively higher number of advanced lesions. Whereas macrophage and smooth muscle cell content did not differ between LRP-deficient mice and control littermates, a 1.7-fold increase in collagen content and 2.3-fold decrease in relative number of CD3+ T cells were observed in lesions from macrophage specific LRP-deficient mice. CONCLUSIONS: Our data demonstrate that independent of its role in lipoprotein uptake, absence of LRP in macrophages resulted in more advanced atherosclerosis and in lesions that contained more collagen and less CD3+ T cells. In contrast to previous in vitro studies, we conclude that macrophage LRP has an atheroprotective potential and may modulate the extracellular matrix in the atherosclerotic lesions.

Animals↗
PubMed2005

Molecular mechanisms of lipoprotein receptor signalling.

The low-density lipoprotein (LDL) receptor is the prototype of a classical endocytosis receptor that mediates the uptake of extracellular ligands. Other members of the LDL receptor gene family, on the other hand, have been shown to regulate intracellular signalling cascades. Among these are the LDL receptor-related protein 1, LRP1, a promiscuous and ubiquitously expressed receptor which is critically involved in a multitude of diverse physiological processes; the Reelin receptors ApoER2 and VLDL receptor, which participate in neuronal development; and megalin, a multifunctional receptor expressed in various epithelia. In this review, we focus on recent developments that highlight similarities and differences between these related receptors and their biological function, and discuss open questions as to the underlying molecular mechanisms.

Animals↗
PubMed2001

Apaf-1 deficiency and neural tube closure defects are found in fog mice.

The forebrain overgrowth mutation (fog) was originally described as a spontaneous autosomal recessive mutation mapping to mouse chromosome 10 that produces forebrain defects, facial defects, and spina bifida. Although the fog mutant has been characterized and available to investigators for several years, the underlying mutation causing the pathology has not been known. Because of its phenotypic resemblance to apoptotic protease activating factor-1 (Apaf-1) knockout mice, we have investigated the possibility that the fog mutation is in the Apaf-1 gene. Allelic complementation, Western blot analysis, and caspase activation assays indicate that fog mutant mice lack Apaf-1 activity. Northern blot and reverse transcription-PCR analysis show that Apaf-1 mRNA is aberrantly processed, resulting in greatly reduced expression levels of normal Apaf-1 mRNA. These findings are strongly suggestive of the fog mutation being a hypomorphic Apaf-1 defect and implicate neural progenitor cell death in the pathogenesis of spina bifida-a common human congenital malformation. Because a complete deficiency in Apaf-1 usually results in perinatal lethality and fog/fog mice more readily survive into adulthood, these mutants serve as a valuable model with which apoptotic cell death can be studied in vivo.

Abnormalities, Multiple↗
PubMed2001

Lipoprotein receptors: beacons to neurons?

Lipoprotein receptors were originally considered simply as cellular transporters for cholesterol and other lipids. This view is rapidly changing. Signaling functions have recently been recognized in several members of the low-density lipoprotein receptor gene family. These Apolipoprotein E receptors are highly expressed in the developing and in the mature nervous system, in which they regulate crucial developmental processes and might also participate in synaptic neurotransmission.

Alzheimer Disease↗
PubMed2001

Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of Apaf-1.

Apoptotic protease-activating factor-1 (Apaf-1), dATP, and procaspase-9 form a multimeric complex that triggers programmed cell death through the activation of caspases upon release of cytochrome c from the mitochondria into the cytosol. Although cell death pathways exist that can bypass the requirement for cytochrome c release and caspase activation, several gene knockout studies have shown that the cytochrome c-mediated apoptotic pathway is critical for neural development. Specifically, the number of neuronal progenitor cells is abnormally increased in Apaf-1-, caspase-9-, caspase-3-deficient mice. However, the role of the cytochrome c cell death pathway for apoptosis of postmitotic, differentiated neurons in the developing brain has not been investigated in vivo. In this study we investigated embryonic neuronal cell death caused by trophic factor deprivation or lack of neurotransmitter release by analyzing Apaf-1/tyrosine kinase receptor A (TrkA) and Apaf-1/Munc-18 double mutant mice. Histological analysis of the double mutants' brains (including cell counting and terminal (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining) reveals that neuronal cell death caused by these stimuli can proceed independent of Apaf-1. We propose that a switch between apoptotic programs (and their respective proteins) characterizes the transition of a neuronal precursor cell from the progenitor pool to the postmitotic population of differentiated neurons.

Animals↗
PubMed2001

The LDL receptor gene family: signaling functions during development.

The traditional views regarding the biological functions of the low-density lipoprotein (LDL) receptor gene family have been revisited recently with new evidence that at least some of the members of this receptor family act as signal-transduction molecules. Known for their role in endocytosis, particularly of their namesake the LDLs, and for their role in the prevention of atherosclerosis, these receptors belong to an ancient family with numerous ligands, effector molecules and functions. Recent evidence implicates this family of receptors in diverse signaling pathways, long-term potentiation and neuronal degeneration.

Animals↗
PubMed2001

Inhibition of synovial plasma extravasation by preemptive administration of an antiinflammatory irrigation solution in the rat knee.

UNLABELLED: Inflammation and hyperalgesia during surgical procedures are caused by the local release of multiple inflammatory mediators. We used a rat knee joint model of acute inflammation (synovial plasma extravasation) to determine whether preemptive intraarticular irrigation of the antiinflammatory drugs ketoprofen, amitriptyline, or oxymetazoline, alone or in combination, can reduce inflammatory soup-induced plasma extravasation. These three drugs were selected because of their abilities to collectively inhibit the inflammatory effects of biogenic amines, eicosanoid production, and the release of neuropeptides from C-fiber terminals. Synovial perfusion of each one of the three drugs 10 min before, and then in combination with, the inflammatory soup (bradykinin, 5-hydroxytryptamine, and mustard oil) did not reduce plasma extravasation. Similarly, two-drug combinations did not significantly reduce inflammatory soup-induced plasma extravasation. The combination of all three drugs (amitriptyline, ketoprofen, and oxymetazoline) produced a dramatic inhibition of plasma extravasation and was more effective than any of the two-drug combinations. A comparison between the preemptive (10 min before inflammatory soup perfusion) and postinflammatory administration (10 min after inflammatory soup perfusion) showed that the postinflammatory administration of the three-drug solution lost all ability to inhibit inflammatory soup-induced plasma extravasation. We conclude that acute synovial inflammation, which is induced and maintained by multiple mediators, can be substantially inhibited only by the preemptive administration of a drug combination that targets multiple inflammatory mediators. IMPLICATIONS: Preemptive, intraarticular irrigation of a combination of multiple antiinflammatory drugs is a novel and potentially effective method for reducing the synovial inflammatory response, such as that during arthroscopy. In this study, a three-drug combination infusion was statistically superior to one- or two-drug infusions in a rat model.

Amitriptyline↗
PubMed2000

Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction.

The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote the endocytosis and lysosomal delivery of these ligands. However, recent genetic experiments in mice have revealed critical functions for two LDL receptor family members, the very low density lipoprotein receptor and the apoE receptor-2, in the transmission of extracellular signals and the activation of intracellular tyrosine kinases. This process regulates neuronal migration and is crucial for brain development. Signaling through these receptors requires the interaction of their cytoplasmic tails with the intracellular adaptor protein Disabled-1 (DAB1). Here, we identify an extended set of cytoplasmic proteins that might also participate in signal transmission by the LDL receptor gene family. Most of these novel proteins are adaptor or scaffold proteins that contain PID or PDZ domains and function in the regulation of mitogen-activated protein kinases, cell adhesion, vesicle trafficking, or neurotransmission. We show that binding of DAB1 interferes with receptor internalization suggesting a mechanism by which signaling through this class of receptors might be regulated. Taken together, these findings imply much broader physiological functions for the LDL receptor family than had previously been appreciated. They form the basis for the elucidation of the molecular pathways by which cells respond to the diversity of ligands that bind to these multifunctional receptors on the cell surface.

Amino Acid Sequence↗
PubMed2000

The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2.

Correct positioning of neurons during embryonic development of the brain depends, among other processes, on the proper transmission of the reelin signal into the migrating cells via the interplay of its receptors with cytoplasmic signal transducers. Cellular components of this signaling pathway characterized to date are cell surface receptors for reelin like apolipoprotein E receptor 2 (ApoER2), very low density lipoprotein receptor (VLDLR), and cadherin-related neuronal receptors, and intracellular components like Disabled-1 and the nonreceptor tyrosine kinase Fyn, which bind to the intracellular domains of the ApoER2 and VLDL receptor or of cadherin-related neuronal receptors, respectively. Here we show that ApoER2, but not VLDLR, also binds the family of JNK-interacting proteins (JIPs), which act as molecular scaffolds for the JNK-signaling pathway. The ApoER2 binding domain on JIP-2 does not overlap with the binding sites for MLK3, MKK7, and JNK. These results suggest that ApoER2 is able to assemble a multiprotein complex containing Disabled-1 and JIPs, together with their binding partners, to the cell surface of neurons. This complex might participate in ApoER2-specific reelin signaling and thus would explain the different phenotype of mice lacking the ApoER2 from that of VLDLR-deficient mice.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Adult Apaf-1-deficient mice exhibit male infertility.

Release of cytochrome c from the mitochondria, and subsequent binding to apoptotic protease-activating factor-1 (Apaf-1), is a key trigger of apoptotic events. A complex composed of Apaf-1, dATP, and cytochrome c activates a series of cytoplasmic proteases called caspases, leading to apoptotic cell death. We have disrupted the Apaf-1 gene in the mouse. Like previous reports on this knockout model, we find that most Apaf-1 mutants die perinatally and frequently exhibit exencephaly and cranioschesis. We additionally find that the neural lesions that develop in the knockout are due to an excess of neural progenitor cells that manifests as early as embryonic day 9.5 in development. In contrast to previous reports on the Apaf-1 knockout mice, we find that 5% of the mutants successfully survive to adulthood. In these survivors, the brain develops normally, but in males, there is degeneration of spermatogonia resulting in the virtual absence of sperm. Thus, cytochrome c-mediated apoptosis is not absolutely required for normal neural development, but is essential for spermatogenesis. These findings strongly suggest that alternative apoptotic pathways work in conjunction with and parallel to Apaf-1 and can modify its effect on programmed cell death.

Adenosine Triphosphate↗
PubMed2000

Apolipoprotein E receptors: linking brain development and Alzheimer's disease.

Alzheimer's disease is a debilitating neurodegenerative disorder that afflicts an increasing part of our ageing population. An isoform of apolipoprotein E, a protein that mediates the transport of lipids and cholesterol in the circulatory system, predisposes carriers of this allele to the common late-onset form of the disease. How this protein is related to a neurodegenerative disorder is an enigma. Mounting evidence indicates that apolipoprotein E receptors, which are abundantly expressed in most neurons in the central nervous system, also fulfill critical functions during brain development and may profoundly influence the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Cellular signalling by lipoprotein receptors.

Lipoprotein receptors are commonly thought merely to mediate the internalization of lipoprotein particles or the exchange of lipids at the cell surface. Recent findings have now implicated these multifunctional receptors in cellular signalling mechanisms that extend beyond simple ligand endocytosis. By mediating the cellular uptake of lipophilic vitamins and hormones, megalin, a member of the LDL receptor gene family, regulates critical hormonal and metabolic processes. Other members of the LDL receptor family interact with cytoplasmic adaptor and scaffold proteins, which allows them to transmit signals directly across the plasma membrane of the target cell. This sheds a new light on the emerging roles of lipoprotein receptors in pathologic disease processes such as Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins.

We have used adenovirus-mediated gene transfer in mice to investigate low density lipoprotein receptor (LDLR) and LDLR-related protein (LRP)-independent mechanisms that control the metabolism of chylomicron and very low density lipoprotein (VLDL) remnants in vivo. Overexpression of receptor-associated protein (RAP) in mice that lack both LRP and LDLR (MX1cre(+)LRP(flox/flox)LDLR(-/-)) in their livers elicited a marked hypertriglyceridemia in addition to the pre-existing hypercholesterolemia in these animals, resulting in a shift in the distribution of plasma lipids from LDL-sized lipoproteins to large VLDL-sized particles. This dramatic increase in plasma lipids was not due to a RAP-mediated inhibition of a unknown hepatic high affinity binding site involved in lipoprotein metabolism, because no RAP binding could be detected in livers of MX1cre(+)LRP(flox/flox)LDLR(-/-) mice using both membrane binding studies and ligand blotting experiments. Remarkably, RAP overexpression also resulted in a 7-fold increase (from 13.6 to 95.6 ng/ml) of circulating, but largely inactive, lipoprotein lipase (LPL). In contrast, plasma hepatic lipase levels and activity were unaffected. In vitro studies showed that RAP binds to LPL with high affinity (K(d) = 5 nM) but does not affect its catalytic activity, in vitro or in vivo. Our findings suggest that an extrahepatic RAP-sensitive process that is independent of the LDLR or LRP is involved in metabolism of triglyceride-rich lipoproteins. There, RAP may affect the functional maturation of LPL, thus causing the accumulation of triglyceride-rich lipoproteins in the circulation.

Animals↗