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Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake

Xu, Hao; Thomas, Michael J; Kaul, Sushma; Kallinger, Rachel; Ouweneel, Amber B; Maruko, Elisa; Oussaada, Sabrina M; Jongejan, Aldo; Cense, Huib A; Nieuwdorp, Max; Serlie, Mireille J; Goldberg, Ira J; Civelek, Mete; Parks, Brian W; Lusis, Aldons J; Knaack, Darcy; Schill, Rebecca L; May, Sarah C; Reho, John J; Grobe, Justin L; Gantner, Benjamin; Sahoo, Daisy; Sorci-Thomas, Mary G
OBJECTIVE: CONCLUSIONS:Overall, these findings reveal a novel and unexpected function for Pcpe2 in modulating SR-BI expression and function as it relates to adipose tissue expansion and cholesterol balance in both mice and humans.
PMID: 34551590
ISSN: 1524-4636
CID: 5026882

A simple, rapid, and sensitive fluorescence-based method to assess triacylglycerol hydrolase activity

Rajan, Sujith; de Guzman, Hazel C; Palaia, Thomas; Goldberg, Ira J; Hussain, M Mahmood
Lipases constitute an important class of water-soluble enzymes that catalyze the hydrolysis of hydrophobic triacylglycerol (TAG). Their enzymatic activity is typically measured using multistep procedures involving isolation and quantification of the hydrolyzed products. We report here a new fluorescence method to measure lipase activity in real time that does not require the separation of substrates from products. We developed this method using adipose triglyceride lipase (ATGL) and lipoprotein lipase (LpL) as model lipases. We first incubated a source of ATGL or LpL with substrate vesicles containing nitrobenzoxadiazole (NBD)-labeled TAG, then measured increases in NBD fluorescence, and calculated enzyme activities. Incorporation of NBD-TAG into phosphatidylcholine (PC) vesicles resulted in some hydrolysis; however, incorporation of phosphatidylinositol into these NBD-TAG/PC vesicles and increasing the ratio of NBD-TAG to PC greatly enhanced substrate hydrolysis. This assay was also useful in measuring the activity of pancreatic lipase and hormone-sensitive lipase. Next, we tested several small-molecule lipase inhibitors and found that orlistat inhibits all lipases, indicating that it is a pan-lipase inhibitor. In short, we describe a simple, rapid, fluorescence-based triacylglycerol hydrolysis assay to assess four major TAG hydrolases: intracellular ATGL and hormone-sensitive lipase, LpL localized at the extracellular endothelium, and pancreatic lipase present in the intestinal lumen. The major advantages of this method are its speed, simplicity, and elimination of product isolation. This assay is potentially applicable to a wide range of lipases, is amenable to high-throughput screening to discover novel modulators of triacylglycerol hydrolases, and can be used for diagnostic purposes.
PMID: 34508728
ISSN: 1539-7262
CID: 5032542

Cardiovascular disease in diabetes, beyond glucose

Eckel, Robert H; Bornfeldt, Karin E; Goldberg, Ira J
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
PMID: 34289375
ISSN: 1932-7420
CID: 5003902

Lipolytic enzymes and free fatty acids at the endothelial interface

Goldberg, Ira J; Cabodevilla, Ainara G; Samovski, Dmitri; Cifarelli, Vincenza; Basu, Debapriya; Abumrad, Nada A
Lipids released from circulating lipoproteins by intravascular action of lipoprotein lipase (LpL) reach parenchymal cells in tissues with a non-fenestrated endothelium by transfer through or around endothelial cells. The actions of LpL are controlled at multiple sites, its synthesis and release by myocytes and adipocytes, its transit and association with the endothelial cell luminal surface, and finally its activation and inhibition by a number of proteins and by its product non-esterified fatty acids. Multiple pathways mediate endothelial transit of lipids into muscle and adipose tissues. These include movement of fatty acids via the endothelial cell fatty acid transporter CD36 and movement of whole or partially LpL-hydrolyzed lipoproteins via other apical endothelial cell receptors such as SR-B1and Alk1. Lipids also likely change the barrier function of the endothelium and operation of the paracellular pathway around endothelial cells. This review summarizes in vitro and in vivo support for the key role of endothelial cells in delivery of lipids and highlights incompletely understood processes that are the focus of active investigation.
PMID: 34130222
ISSN: 1879-1484
CID: 4936762

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.
PMID: 34128469
ISSN: 1558-8238
CID: 4924662

John Calvert Rutledge, MD, 1949-2021

Goldberg, Ira J
PMID: 33760635
ISSN: 1524-4636
CID: 4862182

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice

Voisin, Maud; Shrestha, Elina; Rollet, Claire; Nikain, Cyrus A; Josefs, Tatjana; Mahé, Mélanie; Barrett, Tessa J; Chang, Hye Rim; Ruoff, Rachel; Schneider, Jeffrey A; Garabedian, Michela L; Zoumadakis, Chris; Yun, Chi; Badwan, Bara; Brown, Emily J; Mar, Adam C; Schneider, Robert J; Goldberg, Ira J; Pineda-Torra, Inés; Fisher, Edward A; Garabedian, Michael J
Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
PMID: 33772096
ISSN: 2399-3642
CID: 4823692

Response to Letter to the Editor: "Lipid Management in Patients With Endocrine Disorders: An Endocrine Society Clinical Practice Guideline"

Newman, Connie; Tannock, Lisa R; Goldberg, Ira
PMID: 33484130
ISSN: 1945-7197
CID: 4861852

Atherosclerosis Regression and Cholesterol Efflux in Hypertriglyceridemic Mice

Josefs, Tatjana; Basu, Debapriya; Vaisar, Tomas; Arets, Britt; Kanter, Jenny E; Huggins, Lesley-Ann; Hu, Yunying; Liu, Jianhua; Clouet-Foraison, Noemie; Heinecke, Jay W; Bornfeldt, Karin E; Goldberg, Ira J; Fisher, Edward A
[Figure: see text].
PMID: 33530703
ISSN: 1524-4571
CID: 4850882

Cardiomyocyte Krüppel-Like Factor 5 Promotes De Novo Ceramide Biosynthesis and Contributes to Eccentric Remodeling in Ischemic Cardiomyopathy

Hoffman, Matthew; Palioura, Dimitra; Kyriazis, Ioannis D; Cimini, Maria; Badolia, Rachit; Rajan, Sudarsan; Gao, Erhe; Nikolaidis, Nikolas; Schulze, P Christian; Goldberg, Ira J; Kishore, Raj; Yang, Vincent W; Bannister, Thomas D; Bialkowska, Agnieszka B; Selzman, Craig H; Drakos, Stavros G; Drosatos, Konstantinos
BACKGROUND:We previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure. METHODS:). We identified the involvement of KLF5 in regulating lipid metabolism and ceramide accumulation after MI using liquid chromatography-tandem mass spectrometry, and Western blot and real-time polymerase chain reaction analysis of ceramide metabolism-related genes. We lastly evaluated the effect of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA [reverse tetracycline-controlled transactivator]-KLF5) on cardiac function and ceramide metabolism, and rescued the phenotype using myriocin to inhibit ceramide biosynthesis. RESULTS:mice was not different in control mice. KLF5 ablation suppressed the expression of SPTLC1 and SPTLC2 (serine palmitoyltransferase [SPT] long-chain base subunit ()1 2, respectively), which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are increased in heart failure patients. Consistently, αMHC-rtTA-KLF5 mice showed increased SPTLC1 and SPTLC2 expression, higher myocardial ceramide levels, and systolic dysfunction beginning 2 weeks after KLF5 induction. Treatment of αMHC-rtTA-KLF5 mice with myriocin that inhibits SPT, suppressed myocardial ceramide levels and alleviated systolic dysfunction. CONCLUSIONS:KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.
PMID: 33430631
ISSN: 1524-4539
CID: 4849272