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Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis

Kothari, Vishal; Ho, Tse W W; Cabodevilla, Ainara G; He, Yi; Kramer, Farah; Shimizu-Albergine, Masami; Kanter, Jenny E; Snell-Bergeon, Janet; Fisher, Edward A; Shao, Baohai; Heinecke, Jay W; Wobbrock, Jacob O; Lee, Warren L; Goldberg, Ira J; Vaisar, Tomas; Bornfeldt, Karin E
BACKGROUND/UNASSIGNED:Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.
PMID: 38828596
ISSN: 1524-4571
CID: 5664892

In the Beginning, Lipoproteins Cross the Endothelial Barrier

Goldberg, Ira J; Cabodevilla, Ainara G; Younis, Waqas
Atherosclerosis begins with the infiltration of cholesterol-containing lipoproteins into the arterial wall. White blood cell (WBC)-associated inflammation follows. Despite decades of research using genetic and pharmacologic methods to alter WBC function, in humans, the most effective method to prevent the initiation and progression of disease remains low-density lipoprotein (LDL) reduction. However, additional approaches to reducing cardiovascular disease would be useful as residual risk of events continues even with currently effective LDL-reducing treatments. Some of this residual risk may be due to vascular toxicity of triglyceride-rich lipoproteins (TRLs). Another option is that LDL transcytosis continues, albeit at reduced rates due to lower circulating levels of this lipoprotein. This review will address these two topics. The evidence that TRLs promote atherosclerosis and the processes that allow LDL and TRLs to be taken up by endothelial cells leading to their accumulation with the subendothelial space.
PMID: 38616110
ISSN: 1880-3873
CID: 5664732

Can another lipid, sphingosine-1-phosphate, treat atherosclerosis? [Comment]

Younis, Waqas; Goldberg, Ira J
PMID: 38563326
ISSN: 1755-3245
CID: 5657182

Burden of cardiometabolic risk factors and vascular health

Hamo, Carine E; Schlamp, Florencia; Drenkova, Kamelia; Jindal, Manila; Fadzan, Maja; Akinlonu, Adedoyin; Goldberg, Ira; Garshick, Michael S; Berger, Jeffrey S
BACKGROUND:Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk. METHODS:Adult participants without CVD and various degrees of cardiometabolic risk factor burden (hypertension, diabetes, obesity) were included. Participants underwent brachial vein EC harvesting followed by RNA sequencing. To evaluate the association between cardiometabolic comorbidity burden and outcome transcripts we performed linear regression with multivariable models, adjusting for age, sex, and race/ethnicity. RESULTS:A total of 18 individuals were included in the present analysis (mean age 47 ± 14, 44% female, and 61% White adults). Endothelial cell RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with excellent discrimination in unsupervised hierarchical clustering analysis. Gene ontology enrichment analysis revealed upregulated pathways associated with T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), leukocyte migration (NES= 2.12, p<0.001), regulation of cell-cell adhesion (NES= 1.91, p=0.006). Downregulated pathways of interest included endothelial cell proliferation (NES= -1.68, p=0.03) and response to interleukin-1 (NES= -1.61, p=0.04). Upregulated genes included VCAM1, CEACAM1, ADAM 17, and CD99L2, all with a log-2-fold change >3 and p-adj <0.05. These genes demonstrated a graded increase in mean normalized counts with increasing number of risk factors. CONCLUSIONS:We demonstrate a proinflammatory and pro-adhesive EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into a potential mechanism linking these risk factors with the development of CVD.
PMID: 38199832
ISSN: 1097-6744
CID: 5633802

Continuous glucose monitoring captures glycemic variability in obesity after sleeve gastrectomy: A prospective cohort study

Dorcely, Brenda; DeBermont, Julie; Gujral, Akash; Reid, Migdalia; Vanegas, Sally M.; Popp, Collin J.; Verano, Michael; Jay, Melanie; Schmidt, Ann Marie; Bergman, Michael; Goldberg, Ira J.; Alemán, José O.
Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery. Methods: This was a prospective cohort study of 10 participants with type 2 diabetes compared with 11 participants with non-diabetes undergoing sleeve gastrectomy (SG). At each research visit; before SG, and 6 weeks and 6 months post-SG, body weight, fasting lipid levels, and PG and insulin concentrations during an OGTT were analyzed. Mean amplitude of glycemic excursions (MAGE), a CGM-derived GV index, was analyzed. Results: The 1-h PG correlated with insulin resistance markers, triglyceride/HDL ratio and triglyceride glucose index in both groups before surgery. At 6 months, SG caused 22% weight loss in both groups. Despite a reduction in HbA1c by 3.0 ± 1.3% in the diabetes group (p < 0.01), 1-h PG, and MAGE remained elevated, and the oral disposition index, which represents pancreatic β-cell function, remained reduced in the diabetes group when compared to the non-diabetes group. Conclusions: Elevation of GV markers and reduced disposition index following SG-induced weight loss in the diabetes group underscores persistent β-cell dysfunction and the potential residual risk of diabetes complications.
ISSN: 2055-2238
CID: 5629132

RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia

Gaudet, Daniel; Clifton, Peter; Sullivan, David; Baker, John; Schwabe, Christian; Thackwray, Susan; Scott, Russell; Hamilton, James; Given, Bruce; Melquist, Stacey; Zhou, Rong; Chang, Ting; San Martin, Javier; Watts, Gerald F; Goldberg, Ira J; Knowles, Joshua W; Hegele, Robert A; Ballantyne, Christie M
APOC3-Targeting RNAi for HypertriglyceridemiaThis randomized controlled trial examined the safety and side effects of the small interfering RNA ARO-APOC3 in healthy volunteers and patients with hypertriglyceridemia and chylomicronemia. ARO-APOC3 was associated with few adverse events and no dose-limiting toxicities.
PMID: 38320498
ISSN: 2766-5526
CID: 5632562

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts

Watts, Gerald F; Schwabe, Christian; Scott, Russell; Gladding, Patrick A; Sullivan, David; Baker, John; Clifton, Peter; Hamilton, James; Given, Bruce; Melquist, Stacey; Zhou, Rong; Chang, Ting; San Martin, Javier; Gaudet, Daniel; Goldberg, Ira J; Knowles, Joshua W; Hegele, Robert A; Ballantyne, Christie M
Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. identifier: NCT03747224.
PMID: 37626170
ISSN: 1546-170x
CID: 5598732

Cardiac lipid metabolism, mitochondrial function and heart failure

Da Dalt, Lorenzo; Cabodevilla, Ainara G; Goldberg, Ira J; Norata, Giuseppe Danilo
A fine balance between uptake, storage and the use of high energy fuels, like lipids, is crucial in the homeostasis of different metabolic tissues. Nowhere is this balance more important and more precarious than in the heart. This highly energy demanding muscle normally oxidizes almost all the available substrates to generate energy, with fatty acids being the preferred source under physiological conditions. In patients with cardiomyopathies and heart failure, changes in the main energetic substrate are observed; these hearts often prefer to utilize glucose rather than oxidizing fatty acids. An imbalance between uptake and oxidation of fatty acid can result in cellular lipid accumulation and cytotoxicity. In this review we will focus on the sources and uptake pathways used to direct fatty acids to cardiomyocytes. We will then discuss the intracellular machinery used to either store or oxidize these lipids and explain how disruptions in homeostasis can lead to mitochondrial dysfunction and heart failure. Moreover, we will also discuss the role of cholesterol accumulation in cardiomyocytes. Our discussion will attempt to weave in vitro experiments and in vivo data from mice and humans and use several human diseases to illustrate metabolism gone haywire as a cause of or accomplice to cardiac dysfunction.
PMID: 37392421
ISSN: 1755-3245
CID: 5540662

Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels

Peche, V S; Pietka, T A; Jacome-Sosa, M; Samovski, D; Palacios, H; Chatterjee-Basu, G; Dudley, A C; Beatty, W; Meyer, G A; Goldberg, I J; Abumrad, N A
Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80-100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36-/- mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.
PMID: 37419919
ISSN: 2041-1723
CID: 5536942

Cholesterol efflux pathways hinder KRAS-driven lung tumor progenitor cell expansion

Guilbaud, Emma; Barouillet, Thibault; Ilie, Marius; Borowczyk, Coraline; Ivanov, Stoyan; Sarrazy, Vincent; Vaillant, Nathalie; Ayrault, Marion; Castiglione, Alexia; Rignol, Guylène; Brest, Patrick; Bazioti, Venetia; Zaitsev, Konstantin; Lebrigand, Kevin; Dussaud, Sébastien; Magnone, Virginie; Bertolotto, Corine; Marchetti, Sandrine; Irondelle, Marie; Goldberg, Ira; Huby, Thierry; Westerterp, Marit; Gautier, Emmanuel L; Mari, Bernard; Barbry, Pascal; Hofman, Paul; Yvan-Charvet, Laurent
Cholesterol efflux pathways could be exploited in tumor biology to unravel cancer vulnerabilities. A mouse model of lung-tumor-bearing KRASG12D mutation with specific disruption of cholesterol efflux pathways in epithelial progenitor cells promoted tumor growth. Defective cholesterol efflux in epithelial progenitor cells governed their transcriptional landscape to support their expansion and create a pro-tolerogenic tumor microenvironment (TME). Overexpression of the apolipoprotein A-I, to raise HDL levels, protected these mice from tumor development and dire pathologic consequences. Mechanistically, HDL blunted a positive feedback loop between growth factor signaling pathways and cholesterol efflux pathways that cancer cells hijack to expand. Cholesterol removal therapy with cyclodextrin reduced tumor burden in progressing tumor by suppressing the proliferation and expansion of epithelial progenitor cells of tumor origin. Local and systemic perturbations of cholesterol efflux pathways were confirmed in human lung adenocarcinoma (LUAD). Our results position cholesterol removal therapy as a putative metabolic target in lung cancer progenitor cells.
PMID: 37267915
ISSN: 1875-9777
CID: 5540922