Try a new search

Format these results:

Searched for:

in-biosketch:true

person:goldbi05

Total Results:

301


Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein e-/- mice

Vedantham, Srinivasan; Noh, Hyelim; Ananthakrishnan, Radha; Son, Ni; Hallam, Kellie; Hu, Yunying; Yu, Shuiquing; Shen, Xiaoping; Rosario, Rosa; Lu, Yan; Ravindranath, Thyyar; Drosatos, Konstantinos; Huggins, Lesley Ann; Schmidt, Ann Marie; Goldberg, Ira J; Ramasamy, Ravichandran
OBJECTIVE: There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic. METHODS AND RESULTS: Atherosclerosis development was quantified in 2 lines of transgenic mice expressing human AR (hAR) crossed on the apolipoprotein E knockout background. The transgenes were used to increase the normally low levels of this enzyme in wild-type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin diabetic mice. In addition, pharmacological inhibition of AR reduced lesion size. CONCLUSIONS: Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis
PMCID:3278231
PMID: 21636809
ISSN: 1524-4636
CID: 135542

Triglycerides and heart disease: still a hypothesis?

Goldberg, Ira J; Eckel, Robert H; McPherson, Ruth
The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport, and its tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride-rich lipoproteins, their influence on high-density lipoprotein and low-density lipoprotein, or the underlying diseases that lead to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate very-low-density lipoprotein and their remnants and chylomicron remnants in atherosclerosis development, but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease.
PMCID:3141088
PMID: 21527746
ISSN: 1079-5642
CID: 948622

Diabetes adversely affects macrophages during atherosclerotic plaque regression in mice

Parathath, Saj; Grauer, Lisa; Huang, Li-Shin; Sanson, Marie; Distel, Emilie; Goldberg, Ira J; Fisher, Edward A
OBJECTIVE: Patients with diabetes have increased cardiovascular risk. Atherosclerosis in these patients is often associated with increased plaque macrophages and dyslipidemia. We hypothesized that diabetic atherosclerosis involves processes that impair favorable effects of lipid reduction on plaque macrophages. RESEARCH DESIGN AND METHODS: Reversa mice are LDL receptor-deficient mice that develop atherosclerosis. Their elevated plasma LDL levels are lowered after conditional knockout of the gene encoding microsomal triglyceride transfer protein. We examined the morphologic and molecular changes in atherosclerotic plaques in control and streptozotocin-induced diabetic Reversa mice after LDL lowering. Bone marrow-derived macrophages were also used to study changes mediated by hyperglycemia. RESULTS: Reversa mice were fed a western diet for 16 weeks to develop plaques (baseline). Four weeks after lipid normalization, control (nondiabetic) mice had reduced plasma cholesterol (-77%), plaque cholesterol (-53%), and plaque cells positive for macrophage marker CD68+ (-73%), but increased plaque collagen (+116%) compared with baseline mice. Diabetic mice had similarly reduced plasma cholesterol, but collagen content increased by only 34% compared with baseline; compared with control mice, there were lower reductions in plaque cholesterol (-30%) and CD68+ cells (-41%). Diabetic (vs. control) plaque CD68+ cells also exhibited more oxidant stress and inflammatory gene expression and less polarization toward the anti-inflammatory M2 macrophage state. Many of the findings in vivo were recapitulated by hyperglycemia in mouse bone marrow-derived macrophages. CONCLUSIONS: Diabetes hindered plaque regression in atherosclerotic mice (based on CD68+ plaque content) and favorable changes in plaque macrophage characteristics after the reduction of elevated plasma LDL
PMCID:3114401
PMID: 21562077
ISSN: 1939-327x
CID: 134719

DGAT1 deficiency decreases PPAR expression and does not lead to lipotoxicity in cardiac and skeletal muscle

Liu, Li; Yu, Shuiqing; Khan, Raffay S; Ables, Gene P; Bharadwaj, Kalyani G; Hu, Yunying; Huggins, Lesley A; Eriksson, Jan W; Buckett, Linda K; Turnbull, Andrew V; Ginsberg, Henry N; Blaner, William S; Huang, Li-Shin; Goldberg, Ira J
Diacylglycerol (DAG) acyl transferase 1 (Dgat1) knockout ((-/-)) mice are resistant to high-fat-induced obesity and insulin resistance, but the reasons are unclear. Dgat1(-/-) mice had reduced mRNA levels of all three Ppar genes and genes involved in fatty acid oxidation in the myocardium of Dgat1(-/-) mice. Although DGAT1 converts DAG to triglyceride (TG), tissue levels of DAG were not increased in Dgat1(-/-) mice. Hearts of chow-diet Dgat1(-/-) mice were larger than those of wild-type (WT) mice, but cardiac function was normal. Skeletal muscles from Dgat1(-/-) mice were also larger. Muscle hypertrophy factors phospho-AKT and phospho-mTOR were increased in Dgat1(-/-) cardiac and skeletal muscle. In contrast to muscle, liver from Dgat1(-/-) mice had no reduction in mRNA levels of genes mediating fatty acid oxidation. Glucose uptake was increased in cardiac and skeletal muscle in Dgat1(-/-) mice. Treatment with an inhibitor specific for DGAT1 led to similarly striking reductions in mRNA levels of genes mediating fatty acid oxidation in cardiac and skeletal muscle. These changes were reproduced in cultured myocytes with the DGAT1 inhibitor, which also blocked the increase in mRNA levels of Ppar genes and their targets induced by palmitic acid. Thus, loss of DGAT1 activity in muscles decreases mRNA levels of genes involved in lipid uptake and oxidation.
PMCID:3284165
PMID: 21205704
ISSN: 0022-2275
CID: 948632

Cardiomyocyte lipids impair beta-adrenergic receptor function via PKC activation

Drosatos, Konstantinos; Bharadwaj, Kalyani G; Lymperopoulos, Anastasios; Ikeda, Shota; Khan, Raffay; Hu, Yunying; Agarwal, Rajiv; Yu, Shuiqing; Jiang, Hongfeng; Steinberg, Susan F; Blaner, William S; Koch, Walter J; Goldberg, Ira J
Normal hearts have increased contractility in response to catecholamines. Because several lipids activate PKCs, we hypothesized that excess cellular lipids would inhibit cardiomyocyte responsiveness to adrenergic stimuli. Cardiomyocytes treated with saturated free fatty acids, ceramide, and diacylglycerol had reduced cellular cAMP response to isoproterenol. This was associated with increased PKC activation and reduction of beta-adrenergic receptor (beta-AR) density. Pharmacological and genetic PKC inhibition prevented both palmitate-induced beta-AR insensitivity and the accompanying reduction in cell surface beta-ARs. Mice with excess lipid uptake due to either cardiac-specific overexpression of anchored lipoprotein lipase, PPARgamma, or acyl-CoA synthetase-1 or high-fat diet showed reduced inotropic responsiveness to dobutamine. This was associated with activation of protein kinase C (PKC)alpha or PKCdelta. Thus, several lipids that are increased in the setting of lipotoxicity can produce abnormalities in beta-AR responsiveness. This can be attributed to PKC activation and reduced beta-AR levels.
PMCID:3064003
PMID: 21139071
ISSN: 0193-1849
CID: 948642

Endotoxin activates de novo sphingolipid biosynthesis via nuclear factor kappa B-mediated upregulation of Sptlc2

Chang, Zhi-Qiang; Lee, Su-Yeon; Kim, Hye-Jin; Kim, Jung Ran; Kim, Su-Jung; Hong, In-Kyung; Oh, Byung-Chul; Choi, Cheol-Soo; Goldberg, Ira J; Park, Tae-Sik
Sphingolipids are membrane components and are involved in cell proliferation, apoptosis and metabolic regulation. In this study we investigated whether de novo sphingolipid biosynthesis in macrophages is regulated by inflammatory stimuli. Lipopolysaccharide (LPS) treatment upregulated Sptlc2, a subunit of serine palmitoyltransferase (SPT), mRNA and protein in Raw264.7 and mouse peritoneal macrophages, but Sptlc1, another subunit of SPT, was not altered. SPT activation by LPS elevated cellular levels of ceramides and sphingomyelin (SM). Pharmacological inhibition of nuclear factor kappa B (NFkappaB) prevented LPS-induced upregulation of Sptlc2 while transfection of p65 subunit of NFkappaB upregulated Sptlc2 and increased cellular ceramide levels. In contrast, MAP kinases were not involved in regulation of sphingolipid biosynthesis. Analysis of Sptlc2 promoter and chromatin immunoprecipitation (ChIP) assay showed that NFkappaB binding sites are located in Sptlc2 promoter region. Our results demonstrate that inflammatory stimuli activate de novo sphingolipid biosynthesis via NFkappaB and may play a critical role in lipid metabolism in macrophages.
PMCID:3366150
PMID: 21167294
ISSN: 1098-8823
CID: 948652

Deficiency of lipoprotein lipase in neurons modifies the regulation of energy balance and leads to obesity

Wang, Hong; Astarita, Giuseppe; Taussig, Matthew D; Bharadwaj, Kalyani G; DiPatrizio, Nicholas V; Nave, Klaus-Armin; Piomelli, Daniele; Goldberg, Ira J; Eckel, Robert H
Free fatty acids (FFAs) suppress appetite when injected into the hypothalamus. To examine whether lipoprotein lipase (LPL), a serine hydrolase that releases FFAs from circulating triglyceride (TG)-rich lipoproteins, might contribute to FFA-mediated signaling in the brain, we created neuron-specific LPL-deficient mice. Homozygous mutant (NEXLPL-/-) mice were hyperphagic and became obese by 16 weeks of age. These traits were accompanied by elevations in the hypothalamic orexigenic neuropeptides, AgRP and NPY, and were followed by reductions in metabolic rate. The uptake of TG-rich lipoprotein fatty acids was reduced in the hypothalamus of 3-month-old NEXLPL-/- mice. Moreover, deficiencies in essential fatty acids in the hypothalamus were evident by 3 months, with major deficiencies of long-chain n-3 fatty acids by 12 months. These results indicate that TG-rich lipoproteins are sensed in the brain by an LPL-dependent mechanism and provide lipid signals for the central regulation of body weight and energy balance.
PMCID:3034302
PMID: 21195353
ISSN: 1550-4131
CID: 948662

Sphingolipids and cardiovascular diseases: lipoprotein metabolism, atherosclerosis and cardiomyopathy

Jiang, Xian-Cheng; Goldberg, Ira J; Park, Tae-Sik
Heart disease is widely believed to develop from two pathological processes. Circulating lipoproteins containing the nondegradable lipid, cholesterol, accumulate within the arterial wall and perhaps are oxidized to more toxic lipids. Both lipid accumulation and vascular reaction to the lipids lead to the gradual thickening of the vascular wall. A second major process that in some circumstances is a primary event is the development of a local inflammatory reaction. This might be a reaction to vessel wall injury that accompanies infections, immune disease, and perhaps diabetes and renal failure. In this chapter, we will focus on the relationship between de novo synthesis of sphingolipids and lipid metabolism, atherosclerosis, and cardiomyopathy.
PMID: 21910080
ISSN: 0065-2598
CID: 948672

Unexpected expression pattern for glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) in mouse tissues revealed by positron emission tomography scanning

Olafsen, Tove; Young, Stephen G; Davies, Brandon S J; Beigneux, Anne P; Kenanova, Vania E; Voss, Constance; Young, Glen; Wong, Koon-Pong; Barnes, Richard H 2nd; Tu, Yiping; Weinstein, Michael M; Nobumori, Chika; Huang, Sung-Cheng; Goldberg, Ira J; Bensadoun, Andre; Wu, Anna M; Fong, Loren G
Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), a GPI-anchored endothelial cell protein, binds lipoprotein lipase (LPL) and transports it into the lumen of capillaries where it hydrolyzes triglycerides in lipoproteins. GPIHBP1 is assumed to be expressed mainly within the heart, skeletal muscle, and adipose tissue, the sites where most lipolysis occurs, but the tissue pattern of GPIHBP1 expression has never been evaluated systematically. Because GPIHBP1 is found on the luminal face of capillaries, we predicted that it would be possible to define GPIHBP1 expression patterns with radiolabeled GPIHBP1-specific antibodies and positron emission tomography (PET) scanning. In Gpihbp1(-/-) mice, GPIHBP1-specific antibodies were cleared slowly from the blood, and PET imaging showed retention of the antibodies in the blood pools (heart and great vessels). In Gpihbp1(+/+) mice, the antibodies were cleared extremely rapidly from the blood and, to our surprise, were taken up mainly by lung and liver. Immunofluorescence microscopy confirmed the presence of GPIHBP1 in the capillary endothelium of both lung and liver. In most tissues with high levels of Gpihbp1 expression, Lpl expression was also high, but the lung was an exception (very high Gpihbp1 expression and extremely low Lpl expression). Despite low Lpl transcript levels, however, LPL protein was readily detectable in the lung, suggesting that some of that LPL originates elsewhere and then is captured by GPIHBP1 in the lung. In support of this concept, lung LPL levels were significantly lower in Gpihbp1(-/-) mice than in Gpihbp1(+/+) mice. In addition, Lpl(-/-) mice expressing human LPL exclusively in muscle contained high levels of human LPL in the lung.
PMCID:2998116
PMID: 20889497
ISSN: 0021-9258
CID: 948682

Chylomicron- and VLDL-derived lipids enter the heart through different pathways: in vivo evidence for receptor- and non-receptor-mediated fatty acid uptake

Bharadwaj, Kalyani G; Hiyama, Yaeko; Hu, Yunying; Huggins, Lesley Ann; Ramakrishnan, Rajasekhar; Abumrad, Nada A; Shulman, Gerald I; Blaner, William S; Goldberg, Ira J
Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart-specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36(-/-)), and double knock-out (hLpL0/Cd36(-/-)-DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 +/- 3.8; hLpL0, 36.2 +/- 3.5; Cd36(-/-), 57.7 +/- 5.5 nmol/g, p < 0.05) and an additive effect was observed in the DKO (20.2 +/- 1.4 nmol/g, p < 0.05). Myocardial VLDL-triglyceride (TG) uptake was reduced in the hLpL0 (31 +/- 6%) and Cd36(-/-) (47 +/- 4%) mice with an additive reduction in the DKO (64 +/- 5%) compared with control. However, LpL but not CD36 deficiency decreased VLDL-cholesteryl ester uptake. Endogenously labeled mouse chylomicrons were produced by tamoxifen treatment of beta-actin-MerCreMer/LpL(flox/flox) mice. Induced loss of LpL increased TG levels >10-fold and reduced HDL by >50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by approximately 70% and retinyl ester by approximately 50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDL-derived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins.
PMCID:2992231
PMID: 20852327
ISSN: 0021-9258
CID: 948692