The Niemann-Pick C1 gene interacts with a high-fat diet to promote weight gain through differential regulation of central energy metabolism pathways.

A genome-wide association study (GWAS) reported that common variation in the human Niemann-Pick C1 gene () is associated with morbid adult obesity. This study was confirmed using our BALB/cJ mouse model, whereby heterozygous mice ( ) with decreased gene dosage were susceptible to weight gain when fed a high-fat diet (HFD) compared with homozygous normal mice ( ) fed the same diet. The objective for our current study was to validate this gene-diet interaction using statistical modeling with fitted growth trajectories, conduct body weight analyses for different measures, and define the physiological basis responsible for weight gain.

Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages.

ABCA1 exports excess cholesterol from cells to apoA-I and is essential for HDL synthesis. Genetic studies have shown that ABCA1 protects against cardiovascular disease. We have previously shown that the interaction of apoA-I with ABCA1 activates signaling molecule Janus kinase 2 (JAK2), which optimizes the cholesterol efflux activity of ABCA1.

Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice.

Low-grade chronic inflammation plays an important role in the pathogenesis of obesity-induced insulin resistance. ABCA1 is essential for reverse cholesterol transport and HDL synthesis, and protects against macrophage inflammation. In the present study, the effects of ABCA1 deficiency in hematopoietic cells on diet-induced inflammation and insulin resistance were tested in vivo using bone marrow transplanted (BMT)-WT and BMT-ABCA1(-/-) mice.

ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction.

In addition to triacylglycerols, adipocytes contain a large reserve of unesterified cholesterol. During adipocyte lipolysis and cell death seen during severe obesity and weight loss, free fatty acids and cholesterol become available for uptake and processing by adipose tissue macrophages (ATMs). We hypothesize that ATMs become cholesterol enriched and participate in cholesterol clearance from adipose tissue.

Serum amyloid A and inflammation in diabetic kidney disease and podocytes.

Inflammatory pathways are central mechanisms in diabetic kidney disease (DKD). Serum amyloid A (SAA) is increased by chronic inflammation, but SAA has not been previously evaluated as a potential DKD mediator. The aims of this study were to determine whether SAA is increased in human DKD and corresponding mouse models and to assess effects of SAA on podocyte inflammatory responses.

Genetic modulation of diabetic nephropathy among mouse strains with Ins2 Akita mutation.

Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end-stage renal disease. DN is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation.

Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice.

Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis.

Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase.

Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance.

Copper induces--and copper chelation by tetrathiomolybdate inhibits--endothelial activation in vitro.

Endothelial activation with increased expression of cellular adhesion molecules and chemokines critically contributes to vascular inflammation and atherogenesis. Redox-active transition metal ions play an important role in vascular oxidative stress and inflammation. Therefore, the goal of the present study was to investigate the role of copper in endothelial activation and the potential anti-inflammatory effects of copper chelation by tetrathiomolybdate (TTM) in human aortic endothelial cells (HAECs).

Glomerular cell death and inflammation with high-protein diet and diabetes.

Background: Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo.

Methods: Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold>control); (iii) high glucose (HG, 30.

A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts.

Objective: Factors responsible for the variability in outcomes after lower extremity vein bypass grafting (LEVBG) are poorly understood. Recent evidence has suggested that a single nucleotide polymorphism (SNP) in the promoter region of the p27(Kip1) gene, a cell-cycle regulator, is associated with coronary in-stent restenosis. We hypothesized an association with vein graft patency.

Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits.

We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5% of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase.

Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice.

Endothelial activation, which is characterized by upregulation of cellular adhesion molecules and pro-inflammatory chemokines and cytokines, and consequent monocyte recruitment to the arterial intima are etiologic factors in atherosclerosis. Redox-active transition metal ions, such as copper and iron, may play an important role in endothelial activation by stimulating redox-sensitive cell signaling pathways. We have shown previously that copper chelation by tetrathiomolybdate (TTM) inhibits LPS-induced acute inflammatory responses in vivo.

RNA-binding protein IGF2BP2/IMP2 is required for laminin-β2 mRNA translation and is modulated by glucose concentration.

Laminin-β2 (LAMB2) is a critical component of the glomerular basement membrane as content of LAMB2 in part determines glomerular barrier permeability. Previously, we reported that high concentrations of glucose reduce expression of this laminin subunit at the translational level. The present studies were undertaken to further define systems that control Lamb2 translation and the effect of high glucose on those systems.

Murine norovirus increases atherosclerotic lesion size and macrophages in Ldlr(-/-) mice.

Murine norovirus (MNV) is prevalent in rodent facilities in the United States. Because MNV has a tropism for macrophages and dendritic cells, we hypothesized that it may alter phenotypes of murine models of inflammatory diseases, such as obesity and atherosclerosis. We examined whether MNV infection influences phenotypes associated with diet-induced obesity and atherosclerosis by using Ldlr(-/-) mice.

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice.

Lymphotoxin-α (LTα) is secreted by lymphocytes and acts through tumor necrosis factor-α receptors and the LTβ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT(-/-)) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk.

NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes.

Excess glucose and free fatty acids delivered to adipose tissue causes local inflammation, which contributes to insulin resistance. Glucose and palmitate generate reactive oxygen species (ROS) in adipocytes, leading to monocyte chemotactic factor gene expression. Docosahexaenoate (DHA) has the opposite effect.

Obesity and weight loss result in increased adipose tissue ABCG1 expression in db/db mice.

The prevalence of obesity has reached epidemic proportions and is associated with several co-morbid conditions including diabetes, dyslipidemia, cancer, atherosclerosis and gallstones. Obesity is associated with low systemic inflammation and an accumulation of adipose tissue macrophages (ATMs) that are thought to modulate insulin resistance. ATMs may also modulate adipocyte metabolism and take up lipids released during adipocyte lipolysis and cell death.

S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells: implications for atherosclerosis and adipose tissue inflammation.

Background: S100A9 is constitutively expressed in neutrophils, dendritic cells, and monocytes; is associated with acute and chronic inflammatory conditions; and is implicated in obesity and cardiovascular disease in humans. Most of the constitutively secreted S100A9 is derived from myeloid cells. A recent report demonstrated that mice deficient in S100A9 exhibit reduced atherosclerosis compared with controls and suggested that this effect was due in large part to loss of S100A9 in bone marrow-derived cells.

Direct recruitment of insulin receptor and ERK signaling cascade to insulin-inducible gene loci.

Objective: Insulin receptor (IR) translocates to the nucleus, but its recruitment to gene loci has not been demonstrated. Here, we tested the hypothesis that IR and its downstream mitogenic transducers are corecruited to two prototypic insulin-inducible genes: early growth response 1 (egr-1), involved in mitogenic response, and glucokinase (Gck), encoding a key metabolic enzyme.

Research Design And Methods: We used RNA and chromatin from insulin-treated rat hepatic tumor cell line expressing human insulin receptor (HTC-IR) and livers from lean and insulin-resistant ob/ob glucose-fed mice in quantitative RT-PCR and chromatin immunoprecipitation studies to determine gene expression levels and associated recruitment of RNA polymerase II (Pol II), insulin receptor, and cognate signaling proteins to gene loci, respectively.

In vivo knockdown of nicotinic acetylcholine receptor α1 diminishes aortic atherosclerosis.

Objective: Nicotinic acetylcholine receptor α1 (nAChRα1) was recently identified as a functional cell receptor for urokinase, a potent atherogenic molecule. Here, we test the hypothesis that nAChRα1 plays a role in the pathogenesis of atherosclerosis.

Methods: Apolipoprotein E-deficient mice were initially fed a Western diet for 8 wks.

Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism.

Background: We previously mapped a quantitative trait locus on chromosome 15 in mice contributing to high-density lipoprotein cholesterol and triglyceride levels and now report the identification of the underlying gene.

Methods And Results: We first fine-mapped the locus by studying a series of congenic strains derived from the parental strains BALB/cJ and MRL/MpJ. Analysis of gene expression and sequencing followed by transgenic complementation led to the identification of zinc fingers and homeoboxes 2 (Zhx2), a transcription factor previously implicated in the developmental regulation of alpha-fetoprotein.

Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys.

Accumulation of cholesterol in arterial macrophages may contribute to diabetes-accelerated atherosclerotic cardiovascular disease. The ATP-binding cassette transporter ABCA1 is a cardioprotective membrane protein that mediates cholesterol export from macrophages. Factors elevated in diabetes, such as reactive carbonyls and free fatty acids, destabilize ABCA1 protein in cultured macrophages, raising the possibility that impaired ABCA1 plays an atherogenic role in diabetes.

Integrative genomics identifies DSCR1 (RCAN1) as a novel NFAT-dependent mediator of phenotypic modulation in vascular smooth muscle cells.

Vascular smooth muscle cells (SMCs) display remarkable phenotypic plasticity in response to environmental cues. The nuclear factor of activated T-cells (NFAT) family of transcription factors plays a critical role in vascular pathology. However, known functional NFAT gene targets in vascular SMCs are currently limited.