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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: 5563812

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

Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3)

Ginsberg, Henry N; Goldberg, Ira J
The positive relationship between increased levels of circulating triglycerides and cardiovascular events has been observed for decades. Driven by genetic cohort studies, inhibitors of APOC3 (apolipoprotein C3) and ANGPTL (angiopoietin-like protein) 3 that reduce circulating triglycerides are poised to enter clinical practice. We will review the biology of how inhibition of these 2 proteins affects circulating lipoproteins as well as the current state of clinical development of monoclonal antibodies, antisense oligonucleotides, and silencing RNAs targeting APOC3 and ANGPTL3.
PMID: 36579649
ISSN: 1524-4636
CID: 5447822

Obesity and Overweight: Probing Causes, Consequences, and Novel Therapeutic Approaches Through the American Heart Association's Strategically Focused Research Network

Clark, Jeanne M; Garvey, W Timothy; Niswender, Kevin D; Schmidt, Ann Marie; Ahima, Rexford S; Aleman, Jose O; Battarbee, Ashley N; Beckman, Joshua; Bennett, Wendy L; Brown, Nancy J; Chandler-Laney, Paula; Cox, Nancy; Goldberg, Ira J; Habegger, Kirk M; Harper, Lorie M; Hasty, Alyssa H; Hidalgo, Bertha A; Kim, Sangwon F; Locher, Julie L; Luther, James M; Maruthur, Nisa M; Miller, Edgar R; Sevick, Mary Ann; Wells, Quinn
As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN-designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity-focused investigators and next-step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.
PMID: 36752232
ISSN: 2047-9980
CID: 5420832

"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency"

Oluwadare, Jide; Cabodevilla, Ainara G; Son, Ni-Huiping; Hu, Yunying; Mullick, Adam E; Verano, Michael; Alemán, Jose O; Ramasamy, Ravichandran; Goldberg, Ira J
Lipid accumulation in non-adipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human Neutral Lipid Storage Disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl knockout mice a low- or high-fat diet, we found heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double knockout mice also deficient in either cardiac lipoprotein lipase (LpL) or cluster of differentiation (CD) 36, which is involved in an LpL-independent pathway for fatty acid uptake in the heart. We show neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo fatty acid synthesis. Thus, we conclude pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.
PMID: 36115595
ISSN: 1539-7262
CID: 5336622

Big Fish or No Fish; Eicosapentaenoic Acid and Cardiovascular Disease

Goldberg, Ira J; Gjini, Jana; Fisher, Edward A
Benefits of omega 3 fatty acids for cardiovascular and other diseases have been touted for more than 50 years. The one clear clinical benefit of these lipids is the reduction of circulating levels of triglycerides, making them a useful approach for the prevention of pancreatitis in severely hypertriglyceridemic patients. After a series of spectacularly failed clinical trials that were criticized for the choice of subjects and doses of omega 3 fatty acids used, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using a high dose of icosapent ethyl (IPE) reported a reduction in cardiovascular disease (CVD) events. However, this trial has generated controversy due to the use of mineral oil in the control group and the associated side effects of the IPA. This review will focus on the following topics: What are the epidemiologic data suggesting a benefit of omega 3 fatty acids? What might be the mechanisms for these benefits? Why have the clinical trials failed to resolve whether these fatty acids provide benefit? What choices should a clinician consider?
PMID: 35963632
ISSN: 1558-4410
CID: 5287452

Angiopoietin-like 3: An important protein in regulating lipoprotein levels

Burks, Kendall H; Basu, Debapriya; Goldberg, Ira J; Stitziel, Nathan O
ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and low-density lipoprotein cholesterol. The identification of ANGPTL3 deficiency as a cause of familial combined hypolipidemia in humans hastened the development of anti-ANGPTL3 therapeutic agents, including evinacumab (a monoclonal antibody inhibiting circulating ANGPTL3), vupanorsen (an antisense oligonucleotide [ASO] targeting hepatic ANGPTL3 mRNA for degradation), and others. Advances have also been made in ANGPTL3 vaccination and gene editing strategies, with the former still in preclinical phases and the latter in preparation for Phase 1 trials. Here, we review the discovery of ANGPTL3 as an important regulator of lipoprotein metabolism, molecular characteristics of the protein, mechanisms by which it regulates plasma lipids, and the clinical development of anti-ANGPTL3 agents. The clinical success of therapies inhibiting ANGPTL3 highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia.
PMID: 35999139
ISSN: 1878-1594
CID: 5338242

Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice

Takahashi, Manabu; Yamamuro, Daisuke; Wakabayashi, Tetsuji; Takei, Akihito; Takei, Shoko; Nagashima, Shuichi; Okazaki, Hiroaki; Ebihara, Ken; Yagyu, Hiroaki; Takayanagi, Yuki; Onaka, Tatsushi; Goldberg, Ira J; Ishibashi, Shun
During obesity, tissue macrophages increase in number and become pro-inflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride (TG) in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lepob/ob mice with mice lacking the Lpl gene in myeloid cells (Lplm-/m-) to generate Lplm-/m-;Lepob/ob mice. We found the weight of perigonadal white adipose tissue (WAT) was increased in Lplm-/m-;Lepob/ob mice compared with Lepob/ob mice due to substantial accumulation of both adipose tissue macrophages (ATMs) and collagen that surrounded necrotic adipocytes. In the fibrotic epidydimal WAT of Lplm-/m-;Lepob/ob mice, we observed an increase in collagen VI and high mobility group box 1 (HMGB1), while α-smooth muscle cell actin, a marker of myofibroblasts, was almost undetectable, suggesting that the adipocytes were the major source of the collagens. Furthermore the ATMs from Lplm-/m-;Lepob/ob mice showed increased expression of genes related to fibrosis and inflammation. In addition, we determined Lplm-/m-;Lepob/ob mice were more hypertriglyceridemic than Lepob/ob mice. Lplm-/m-;Lepob/ob mice also showed slower weight gain than Lepob/ob mice, which was primarily due to reduced food intake. In conclusion, we discovered that the loss of myeloid Lpl led to extensive fibrosis of perigonadal WAT and hypertriglyceridemia. In addition to illustrating an important role of macrophage LPL in regulation of circulating TG levels, these data show that macrophage LPL protects against fibrosis in obese adipose tissues.
PMID: 35926714
ISSN: 1083-351x
CID: 5288252