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Inflammation reprogramming and immunomodulation: Next-generation treatments for atherosclerosis

Choudhury, Robin P; Hargreaves, Rupen; Chai, Jason; Fisher, Edward A
The current generation of highly successful atherosclerosis treatments, such as low-density lipoprotein (LDL)-cholesterol reduction, blood pressure management, and smoking cessation, has largely focused on ameliorating factors perceived to drive incident disease and its complications. The adverse contributions of these factors have typically been identified through epidemiological studies. The therapeutic strategies that arose in response focused on risk factors for disease development and tended to overlook the fact that patients already have established disease, by the time of presentation. However, by capitalizing on contemporary biological knowledge and technologies, it is becoming increasingly possible to shift from a model based on population-derived risk factor management to next-generation treatments (including monoclonal antibodies, small interfering RNA [siRNA], mRNA, epigenetic reprogramming, and gene editing) for atherosclerosis that are tailored to patient-level disease processes, informed by mechanistic characterization, offer potential to reverse or regress disease, and incorporate systems-level interventions that extend beyond the atherosclerotic plaque.
PMID: 40782797
ISSN: 2666-3791
CID: 5905642

IL1β Secretion by Epididymal White Adipose Tissue Macrophages Regulates Myelopoiesis and Plaque Inflammation in Obese Mice and in Caloric Restriction [Letter]

Li, Zhixing; Krautter, Franziska; La Forest, Maxwell; Fisher, Edward A
PMCID:12286714
PMID: 40567227
ISSN: 1524-4636
CID: 5906322

Cycling of metabolic states and metabolites as drivers of atherosclerosis

Krautter, Franziska; Fisher, Edward A
PURPOSE OF REVIEW/OBJECTIVE:Cardiovascular diseases (CVDs) are a leading cause of death worldwide. While it is well known that obesity, dyslipidemia and diabetes are major risk factors of CVD, observational clinical studies have shown that variability in body weight, circulating LDL-cholesterol (LDL-C) or glucose levels further increase this risk. The underlying mechanisms, however, leading to increased risk of CVD due to metabolic cycling are not well understood. RECENT FINDINGS/RESULTS:Recent studies have shown that metabolic cycling can cause reprogramming of immune cells and their progenitors. Weight, LDL-C, or glucose cycling induced myelopoiesis, monocytosis and/or altered immune cell functions. This resulted in a heightened immune response, ultimately worsening atherosclerosis. SUMMARY/CONCLUSIONS:Even though there are differences in how metabolic cycling is measured in clinical and basic research studies, the conclusion remains the same: metabolic cycling increases CVD severity. Some studies have highlighted the role of reprogramming of myeloid cells and their progenitors in progression of atherosclerosis due to metabolic cycling, but further research is required to better understand the mechanisms behind it.
PMID: 40737138
ISSN: 1473-6535
CID: 5903542

Caloric Restriction Promotes Resolution of Atherosclerosis in Obese Mice, while Weight Regain Accelerates its Progression

Scolaro, Bianca; Krautter, Franziska; Brown, Emily J; Guha Ray, Aleepta; Kalev-Altman, Rotem; Petitjean, Marie; Delbare, Sofie; Donahoe, Casey; Pena, Stephanie; Garabedian, Michela L; Nikain, Cyrus A; Laskou, Maria; Tufanli, Ozlem; Hannemann, Carmen; Aouadi, Myriam; Weinstock, Ada; Fisher, Edward A
While weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.
PMID: 40627456
ISSN: 1558-8238
CID: 5890642

Effect of complete, lifelong ANGPTL3 deficiency on triglyceride-rich lipoprotein kinetics

Fappi, Alan; Patterson, Bruce W; Burks, Kendal H; Davidson, Nicholas O; Vaisar, Tomas; Kanter, Jenny E; Bornfeldt, Karin E; Fisher, Edward A; Goldberg, Ira J; Stitziel, Nathan O; Mittendorfer, Bettina
Angiopoietin-like 3 (ANGPTL3) inhibits lipases that hydrolyze triglycerides (TGs) in TG-rich lipoproteins (TRLs). We evaluated TRL-TGs, TRL particle (apolipoprotein B), palmitate, and glucose kinetics during a mixed-meal test that included intravenous and oral tracer administrations in people with extremely rare compound heterozygous ANGTPL3 loss-of-function mutations (ANGPTL3-/- group, n = 3) and matched control participants (n = 7). Multi-organ (liver, muscle, and adipose tissue) insulin sensitivity was evaluated with a two-step hyperinsulinemic-euglycemic clamp procedure and glucose and palmitate tracer infusions. We find that plasma TG and TRL particle concentrations are more than 10-fold lower in the ANGPTL3-/- than in the control group due to both markedly reduced liver-derived TRL particle and TG secretion rates combined with increased plasma clearance of both liver- and gut-derived TRLs. Palmitate and glucose kinetics during the meal test are not different between the groups. We conclude that the biological function of ANGPTL3 reaches beyond inhibiting intravascular lipase activity.
PMID: 40446802
ISSN: 2666-3791
CID: 5854562

Radiolabeling lipoproteins to study and manage disease

Pérez-Medina, Carlos; Fisher, Edward A; Fayad, Zahi A; Mulder, Willem J M; Teunissen, Abraham J P
PURPOSE/OBJECTIVE:Lipoproteins are endogenous nanoparticles with essential roles in lipid transport and inflammation. Lipoproteins are also valuable in diagnosing and treating disease. For instance, certain lipoproteins are overexpressed in patients with atherosclerotic cardiovascular disease, and reconstituted lipoproteins have been extensively used for drug delivery. Radiolabeling has proven an especially powerful approach for studying and therapeutically exploiting lipoproteins. This review details how radiochemistry and nuclear imaging can facilitate the study of lipoproteins in health and disease. Among other topics, we discuss approaches for radiolabeling lipoproteins and detail how these have helped advance our understanding of lipoprotein biology and the diagnosis and treatment of diseases, including atherosclerosis, cancer, and hypercholesteremia. METHODS:We performed an extensive literature search on all peer-reviewed studies involving radiolabeled lipoproteins and selected representative examples to provide a high-level overview of the most important discoveries and technological advancements. RESULTS:More than 200 peer-reviewed papers involved radiolabeled lipoproteins, spanning mechanistic, diagnostic, and therapeutic studies across a wide range of diseases. CONCLUSION/CONCLUSIONS:Radiolabeling has been critical in advancing our understanding of lipoprotein biology and leveraging these nanomaterials for diagnosing and treating disease.
PMID: 40293448
ISSN: 1619-7089
CID: 5833132

High-Density Lipoprotein Lipid and Protein Cargo and Cholesterol Efflux Capacity Before and After Bariatric Surgery

Zahid, Sohail; Schlamp, Florencia; Gildea, Michael A; Lin, Bing-Xue; Chaloemtoem, Ariya; Falis, Marcin; Parikh, Manish; Fisher, Edward A; Hornemann, Thorsten; Vaisar, Tomas; Heffron, Sean P
BACKGROUND/UNASSIGNED:Cholesterol efflux capacity (CEC) of HDL (high-density lipoprotein) is inversely associated with incident cardiovascular events, independent of HDL cholesterol. Obesity is characterized by low HDL cholesterol and impaired HDL function, such as CEC. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), broadly leads to improved cardiovascular outcomes, but impacts on risk factors differ by procedure, with greater improvements in weight loss, blood pressure, and glycemic control after RYGB, but greater improvements in HDL cholesterol and CEC levels after SG. This study sought to determine effects of RYGB and SG on HDL protein and lipid cargo and investigate associations with CEC changes. METHODS/UNASSIGNED:We prospectively studied nondiabetic, premenopausal Hispanic women with severe obesity not using lipid medications undergoing RYGB (n=31) or SG (n=36). Anthropometric measurements and blood sampling were obtained before and at 6 and 12 months after surgery. HDL was isolated from plasma, and quantitative proteomic and lipidomic assessments were performed with LC-MS/MS (liquid chromatography with tandem mass spectrometry). CEC was assessed ex vivo using apoB-depleted serum. RESULTS/UNASSIGNED:Participants experienced similar, significant weight loss over 12 months following bariatric surgery (38.0±10.4 kg) regardless of the procedure. Relative quantities of 47 proteins (34 increased, 13 decreased) and 150 lipids (71 increased, 79 decreased) carried on HDL were significantly altered following either surgical procedure. Proteins with similar aggregate response patterns were clustered into 15 groups (5 increased, 5 decreased, 5 minimal change) and lipids with similar aggregate responses into 25 groups (7 increased, 11 decreased, 7 minimal change). Network mediation analyses suggested that changes in 4 protein and 2 lipid clusters mediated changes in ABCA1 (ATP-binding cassette transporter A1) CEC and that 1 lipid cluster mediated changes in non-ABCA1 CEC. The protein and lipid clusters that mediated changes in CEC were distinct between SG and RYGB. CONCLUSIONS/UNASSIGNED:Bariatric surgery produces substantial changes in HDL lipid and protein cargo, and specific changes may mediate changes in HDL function in CEC. Further study of these mechanisms may lead to improved interventions to reduce cardiovascular risk in patients with obesity.
PMID: 39744840
ISSN: 1524-4636
CID: 5778262

Sex differences in murine MASH induced by a fructose-palmitate-cholesterol-enriched diet

Arivazhagan, Lakshmi; Delbare, Sofie; Wilson, Robin A; Manigrasso, Michaele B; Zhou, Boyan; Ruiz, Henry H; Mangar, Kaamashri; Higa, Ryoko; Brown, Emily; Li, Huilin; Garabedian, Michael J; Ramasamy, Ravichandran; Moore, Kathryn J; Fisher, Edward A; Theise, Neil D; Schmidt, Ann Marie
BACKGROUND & AIMS/UNASSIGNED:Metabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high-fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. METHODS/UNASSIGNED:standard chow for 16 weeks (n = 40 mice). At sacrifice, plasma and liver were retrieved, the latter for single-nucleus RNA sequencing. Publicly available data sets of human male and female MASH liver were probed. RESULTS/UNASSIGNED:0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the standard chow. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts. CONCLUSIONS/UNASSIGNED:Molecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female individuals in MAFLD/MASH studies and clinical trials. IMPACT AND IMPLICATIONS/UNASSIGNED:male patients with MASH. These results highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.
PMCID:11795143
PMID: 39911943
ISSN: 2589-5559
CID: 5784202

Variation in lipoprotein(a) response to potent lipid lowering: The role of apolipoprotein (a) isoform size

Akinlonu, Adedoyin; Boffa, Michael B; Lyu, Chen; Zhong, Judy; Jindal, Manila; Fadzan, Maja; Garshick, Michael S; Schwartzbard, Arthur; Weintraub, Howard S; Bredefeld, Cindy; Newman, Jonathan D; Fisher, Edward A; Koschinsky, Marlys L; Goldberg, Ira J; Berger, Jeffrey S
BACKGROUND:Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. METHODS:CHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) >100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein (a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days. RESULTS:Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < 0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < 0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = 0.59), apo(a) size directly correlated with Lp(a) reduction (P < 0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < 0.001). CONCLUSION/CONCLUSIONS:Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.
PMID: 39828454
ISSN: 1933-2874
CID: 5777992

Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids

Barnhart, Shelley; Shimizu-Albergine, Masami; Kedar, Eyal; Kothari, Vishal; Shao, Baohai; Krueger, Melissa; Hsu, Cheng-Chieh; Tang, Jingjing; Kanter, Jenny E; Kramer, Farah; Djukovic, Danijel; Pascua, Vadim; Loo, Yueh-Ming; Colonna, Lucrezia; Van den Bogaerde, Sadie J; An, Jie; Gale, Michael; Reue, Karen; Fisher, Edward A; Gharib, Sina A; Elkon, Keith B; Bornfeldt, Karin E
Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.
PMID: 39675509
ISSN: 1539-7262
CID: 5764072