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Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation

Cabodevilla, Ainara G; Tang, Songtao; Lee, Sungwoon; Mullick, Adam E; Aleman, Jose O; Hussain, M Mahmood; Sessa, William C; Abumrad, Nada A; Goldberg, Ira J
Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.
PMCID:8203467
PMID: 34128469
ISSN: 1558-8238
CID: 4924662

Author Correction: Obesity and ethnicity alter gene expression in skin

Walker, Jeanne M; Garcet, Sandra; Aleman, Jose O; Mason, Christopher E; Danko, David; Butler, Daniel; Zuffa, Simone; Swann, Jonathan R; Krueger, James; Breslow, Jan L; Holt, Peter R
PMID: 33790371
ISSN: 2045-2322
CID: 4862322

PPARγ agonists delay age-associated metabolic disease and extend longevity

Xu, Lingyan; Ma, Xinran; Verma, Narendra; Perie, Luce; Pendse, Jay; Shamloo, Sama; Marie Josephson, Anne; Wang, Dongmei; Qiu, Jin; Guo, Mingwei; Ping, Xiaodan; Allen, Michele; Noguchi, Audrey; Springer, Danielle; Shen, Fei; Liu, Caizhi; Zhang, Shiwei; Li, Lingyu; Li, Jin; Xiao, Junjie; Lu, Jian; Du, Zhenyu; Luo, Jian; Aleman, Jose O; Leucht, Philipp; Mueller, Elisabetta
Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.
PMCID:7681041
PMID: 33219735
ISSN: 1474-9726
CID: 4679992

Lipoprotein insulin resistance score in nondiabetic patients with obesity after bariatric surgery

Zhang, Ruina; Lin, BingXue; Parikh, Manish; Fisher, Edward A; Berger, Jeffrey S; Aleman, Jose O; Heffron, Sean P
BACKGROUND:Lipoprotein insulin resistance (LPIR) score is a composite biomarker representative of atherogenic dyslipidemia characteristic of early insulin resistance. It is elevated in obesity and may provide information not captured in glycosylated hemoglobin and homeostatic model assessment for insulin resistance. While bariatric surgery reduces diabetes incidence and resolves metabolic syndrome, the effect of bariatric surgery on LPIR is untested. OBJECTIVES/OBJECTIVE:We sought to assess the effects of Roux-en-Y gastric bypass and sleeve gastrectomy on LPIR in nondiabetic women with obesity. SETTING/METHODS:Nonsmoking, nondiabetic, premenopausal Hispanic women, age ≥18 years, undergoing Roux-en-Y gastric bypass or sleeve gastrectomy at Bellevue Hospital were recruited for a prospective observational study. METHODS:Anthropometric measures and blood sampling were performed preoperatively and at 6 and 12 months postoperatively. LPIR was measured by nuclear magnetic resonance spectroscopy. RESULTS:. LPIR was reduced by 35 ± 4% and 46 ± 4% at 6 and 12 months after surgery, respectively, with no difference by procedure. Twenty-seven of 53 patients met International Diabetes Federation criteria for metabolic syndrome preoperatively and had concomitant higher homeostatic model assessment for insulin resistance, glycosylated hemoglobin, nonhigh-density lipoprotein-cholesterol and LPIR. Twenty-five of 27 patients experienced resolution of metabolic syndrome postoperatively. Concordantly, the preoperative differences in homeostatic model assessment for insulin resistance, glycosylated hemoglobin, and nonhigh-density lipoprotein-cholesterol between those with and without metabolic syndrome resolved at 6 and 12 months. In contrast, patients with metabolic syndrome preoperatively exhibited greater LPIR scores at 6 and 12 months postoperatively. CONCLUSION/CONCLUSIONS:This is the first study to demonstrate improvement in insulin resistance, as measured by LPIR, after bariatric surgery with no difference by procedure. This measure, but not traditional markers, was persistently higher in patients with a preoperative metabolic syndrome diagnosis, despite resolution of the condition.
PMID: 32636175
ISSN: 1878-7533
CID: 4516982

Obesity and ethnicity alter gene expression in skin

Walker, Jeanne M; Garcet, Sandra; Aleman, Jose O; Mason, Christopher E; Danko, David; Zuffa, Simone; Swann, Jonathan R; Krueger, James; Breslow, Jan L; Holt, Peter R
Obesity is accompanied by dysfunction of many organs, but effects on the skin have received little attention. We studied differences in epithelial thickness by histology and gene expression by Affymetrix gene arrays and PCR in the skin of 10 obese (BMI 35-50) and 10 normal weight (BMI 18.5-26.9) postmenopausal women paired by age and ethnicity. Epidermal thickness did not differ with obesity but the expression of genes encoding proteins associated with skin blood supply and wound healing were altered. In the obese, many gene expression pathways were broadly downregulated and subdermal fat showed pronounced inflammation. There were no changes in skin microbiota or metabolites. African American subjects differed from European Americans with a trend to increased epidermal thickening. In obese African Americans, compared to obese European Americans, we observed altered gene expression that may explain known differences in water content and stress response. African Americans showed markedly lower expression of the gene encoding the cystic fibrosis transmembrane regulator characteristic of the disease cystic fibrosis. The results from this preliminary study may explain the functional changes found in the skin of obese subjects and African Americans.
PMCID:7442822
PMID: 32826922
ISSN: 2045-2322
CID: 4581502

PPAR gamma agonists delay age-associated metabolic disease and extend longevity

Xu, Lingyan; Ma, Xinran; Verma, Narendra; Perie, Luce; Pendse, Jay; Shamloo, Sama; Josephson, Anne Marie; Wang, Dongmei; Qiu, Jin; Guo, Mingwei; Ping, Xiaodan; Allen, Michele; Noguchi, Audrey; Springer, Danielle; Shen, Fei; Liu, Caizhi; Zhang, Shiwei; Li, Lingyu; Li, Jin; Xiao, Junjie; Lu, Jian; Du, Zhenyu; Luo, Jian; Aleman, Jose O.; Leucht, Philipp; Mueller, Elisabetta
ISI:000590868800001
ISSN: 1474-9718
CID: 4688412

Surgical and medical weight loss threshold dictates decreases in knee osteoarthritis pain but not reductions in inflammatory biomarkers [Meeting Abstract]

Bomfim, F; Chen, S; Zak, S; Jazrawi, T; Kundler, M; Qie, V; Peralta, L; Aleman, J; Ren-Fielding, C; Lofton, H; Patel, J; Attur, M; Abramson, S B; Samuels, J
Background/Purpose : Weight loss in obese patients can reduce knee osteoarthritis (OA) pain, even when physical therapy and intra-articular injections have failed. The impacts of either non-surgical or surgical weight loss on knee OA pain have been reported separately, but few studies have assessed them conjointly. While the decrease in mechanical load helps, the contribution of metabolic changes is less clear. We aimed to compare biomarker changes with weight loss as predictors of knee pain improvement, and consider a threshold of total weight loss necessary for these changes. Methods : Patients from the NYU Langone Weight Management program were screened for knee pain prior to bariatric surgery or the start of a medical weight loss (MWL) regimen. We excluded patients with autoimmune disease, recent malignancy, recent intra-articular knee injections, and lack of OA by Kellgren-Lawrence (KL) x-ray grading. The BMI, Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain, and blood samples were obtained at baseline and 1, 3, 6 and 12 months for evaluation of pain and biomarker levels. Results : Of 140 patients screened, 81 were eligible and enrolled (82.7% female; BMI 45.2+/-9.6 kg/m2, 31-74; age 52+/-12 years, 30-80). A total of 49 patients had surgery (10 bypass, 30 sleeve, 9 LapBand) and 24 medical weight loss. 33 patients completed visits up to 6 months (2 bypass, 18 sleeve, 6 LapBand, 7 MWL). By 1 month, the surgical patients had lost much more total weight than the MWL group (9.8% vs 4.1 %, p=0.001), and realized marked pain relief (p< 0.001). By 6 months both groups had continued to lose weight, proportionately greater for surgical patients with further pain improvement. (Figure 1) Leptin levels dropped at 1 and then 6 months with both methods of weight loss. The pro-inflammatory protein IL-1Ra decreased significantly by 6 months in the bariatric patients, but increased with the medical regimen across both time points. Soluble vascular adhesion protein 1 (sVAP-1), another pro-inflammatory protein that facilitates leukocyte infiltration, decreased at both the 1 and 6 month intervals -but much more in MWL than in surgical patients. Consistent with the literature, the anti-inflammatory soluble receptor for advanced glycation endproducts (sRAGE) mirrored KOOS pain improvement only in surgical patients and stabilized after 1 month, but did not change in the MWL group. (Table 1) In a subgroup analysis, the 14 surgical patients who lost at least 10% of Figure 1. Surgical and medical outcomes for % total weight loss (TWL), knee pain and biomarkers Table 1. total weight by 1 month had significantly less pain at 6 months than the 12 who did not meet the threshold (DELTAKOOS 47.5 vs 29.9) but the biomarker levels were similar. (Figure 2) Conclusion : Surgical and medically supervised weight loss both lead to significant decreases in adiposity, but only those having bariatric surgery realize significant pain relief. The anatomical changes of surgical (vs. medical) weight loss result in different metabolic cascades given divergent biomarker trends. Bariatric patients who lose more than 10 percent of total body weight within the first month are more likely to have better pain relief by 6 months, but the biomarker changes reflect anatomic intervention -and are not dependent on the degree of surgical weight loss
EMBASE:633059646
ISSN: 2326-5205
CID: 4633472

The effects of trans-resveratrol on insulin resistance, inflammation, and microbiota in men with the metabolic syndrome: A pilot randomized, placebo-controlled clinical trial

Walker, Jeanne M; Eckardt, Patricia; Aleman, Jose O; da Rosa, Joel Correa; Liang, Yupu; Iizumi, Tadasu; Etheve, Stephane; Blaser, Martin J; L Breslow, Jan; Holt, Peter R
Background and Aim/UNASSIGNED:The metabolic syndrome (MetS) is a pathological condition comprised of abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. It has become a major threat globally, resulting in rapidly increasing rates of diabetes, coronary heart disease, and stroke. The polyphenol resveratrol (RES) is believed to improve glucose homeostasis and insulin resistance by activating sirtuin, which acetylates and coactivates downstream targets and affects glucose and lipid homeostasis in the liver, insulin secretion in the pancreas, and glucose uptake in skeletal muscle. We studied the effects of RES on insulin resistance, glucose homeostasis, and concomitant effects on adipose tissue metabolism and fecal microbiota in insulin-resistant subjects with the MetS. Methods/UNASSIGNED:A total of 28 obese men with the MetS were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive RES 1 g orally twice daily or placebo while kept weight stable and consuming a western-style diet. At baseline, and after 30 days of RES or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2-h oral glucose tolerance test (GTT), resting energy expenditure, daily blood pressure monitoring, abdominal adipose tissue biopsy, and fecal and blood collections. Results/UNASSIGNED:. Conclusions/UNASSIGNED:RES 2 g administered orally to obese men with MetS and insulin resistance marginally altered glucose homeostasis. However, in a small group of Caucasians, insulin resistance and glucose homeostasis improved. No concomitant changes in adipose tissue metabolism occurred, but fecal microbiota showed RES-induced changes. Relevance for Patients/UNASSIGNED:The MetS increases the risk of diabetes, heart disease, and stroke. A major component of the syndrome is insulin resistance, resulting in systemic inflammation and hyperinsulinemia. The primary treatment consists of lifestyle changes, improved diet, and increased physical activity. This is often unsuccessful. In this study, RES was well tolerated. In Caucasian men, it significantly improved insulin sensitivity and glucose homeostasis. Similar results were found in studies that consisted exclusively of Caucasian men. However, RES presents a novel addition to the current treatment of the MetS and its sequelae.
PMID: 30873501
ISSN: 2424-810x
CID: 3733472

An integrated adipose-tissue-on-chip nanoplasmonic biosensing platform for investigating obesity-associated inflammation

Zhu, Jingyi; He, Jiacheng; Verano, Michael; Brimmo, Ayoola T; Glia, Ayoub; Qasaimeh, Mohammad A; Chen, Pengyu; Aleman, Jose O; Chen, Weiqiang
Although many advanced biosensing techniques have been proposed for cytokine profiling, there are no clinically available methods that integrate high-resolution immune cell monitoring and in situ multiplexed cytokine detection together in a biomimetic tissue microenvironment. The primary challenge arises due to the lack of suitable label-free sensing techniques and difficulty for sensor integration. In this work, we demonstrated a novel integration of a localized-surface plasmon resonance (LSPR)-based biosensor with a biomimetic microfluidic 'adipose-tissue-on-chip' platform for an in situ label-free, high-throughput and multiplexed cytokine secretion analysis of obese adipose tissue. Using our established adipose-tissue-on-chip platform, we were able to monitor the adipose tissue initiation, differentiation, and maturation and simulate the hallmark formation of crown-like structures (CLSs) during pro-inflammatory stimulation. With integrated antibody-conjugated LSPR barcode sensor arrays, our platform enables simultaneous multiplexed measurements of pro-inflammatory (IL-6 and TNF-α) and anti-inflammatory (IL-10 and IL-4) cytokines secreted by the adipocytes and macrophages. As a result, our adipose-tissue-on-chip platform is capable of identifying stage-specific cytokine secretion profiles from a complex milieu during obesity progression, highlighting its potential as a high-throughput preclinical readout for personalized obesity treatment strategies.
PMID: 30302487
ISSN: 1473-0189
CID: 3334952

The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction: JACC State-of-the-Art Review

Newman, Jonathan D; Vani, Anish K; Aleman, Jose O; Weintraub, Howard S; Berger, Jeffrey S; Schwartzbard, Arthur Z
Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Despite improved risk factor control, however, adults with T2D continue to experience substantial excess CVD risk. Until recently, however, improved glycemic control has not been associated with robust macrovascular benefit. The advent of 2 new classes of antihyperglycemic agents, the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, and their respective large cardiovascular outcome trials, has led to a paradigm shift in how cardiologists and heath care practitioners conceptualize T2D treatment. Herein, the authors review the recent trial evidence, the potential mechanisms of action of the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, safety concerns, and their use for the primary prevention of CVD as well as in diabetic patients with impaired renal function and heart failure.
PMID: 30286929
ISSN: 1558-3597
CID: 3329052