Hyperlipidemic Environment Research Articles

Impact of Short-Term Lipid Overload on Whole-Body Physiology.

Complex metabolic diseases due to overnutrition such as obesity, type 2 diabetes, and fatty liver disease are a major burden on the healthcare system worldwide. Current research primarily focuses on disease endpoints and trying to understand underlying mechanisms at relatively late stages of the diseases, when irreversible damage is already done. However, complex interactions between physiological systems during disease development create a problem regarding how to build cause-and-effect relationships. Therefore, it is essential to understand the early pathophysiological effects of overnutrition, which can help us understand the origin of the disease and to design better treatment strategies. Here, we focus on early metabolic events in response to high-fat diets (HFD) in rodents. Interestingly, insulin resistance, fatty liver, and obesity-promoting systemic inflammatory responses are evident within a week when mice are given consecutive HFD meals. However, as shown in human studies, these effects are usually not visible after a single meal. Overall, these results suggest that sustained HFD-intake within days can create a hyperlipidemic environment, globally remodeling metabolism in all affected organs and resembling some of the important disease features.

FDA-approved polypeptide PTH 1-34 impedes palmitic acid-mediated osteoblasts dysfunction by promoting its differentiation and thereby improving skeletal health.

Excessive consumption of saturated fatty acids creates a debilitating cellular environment that hinders the normal function and survival of osteoblasts, contributing to bone metabolic disorders such as osteoporosis. The FDA-approved polypeptide PTH 1-34 is a well-established therapy for post-menopausal osteoporosis, yet its protective effects in a palmitic acid (PA)-rich hyperlipidemic environment are not well understood. This study investigates the impact of PTH 1-34 on PA-induced cellular responses in osteoblasts. Experiments were conducted on mouse and human-derived osteoblasts as well as C57BL/6J male mice. PA was found to suppress osteoblast differentiation, increase apoptosis, and disrupt autophagy, and thereby impair cellular health. Conversely, PTH 1-34 enhanced cellular health by counteracting these effects. At the molecular level, PTH 1-34 exerted its bioactivity by modulating PTH signaling components such as cAMP and CREB. Impaired osteogenic differentiation was restored by modulating bone-anabolic genes. PTH 1-34 also improved mitochondrial health by preserving mitochondrial membrane potential and maintaining the Bax/Bcl2 ratio, thereby improving cellular viability. Additionally, PTH 1-34 regulated autophagic processes, as evidenced by balanced p62 and LC3 levels, further validated using the autophagy inhibitor Bafilomycin A1. In vivo studies in C57BL/6J male mice corroborated these findings. PTH 1-34 reversed the PA action by maintaining osteoblast number and function. This study establishes the protective role of PTH 1-34 in safeguarding osteoblasts from lipotoxicity caused by excessive PA accumulation, highlighting its potential repurposing for patients with lipid-induced skeletal dysfunctions. The new data underscores the therapeutic versatility of the FDA-approved polypeptide PTH 1-34 in managing lipid-related bone health issues.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway

BackgroundHyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia.MethodsIn this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation.ResultsOur findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression.ConclusionsThese results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Gender Specific Effects of Nr4a1 in Obese Mice

A central aspect of type 2 diabetes disease progression is impaired functional β-cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the β-cell. Nr4a1 expression is decreased in the β-cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetics. Here we demonstrate sex specific effects of β-cell specific Nr4a1 deletion under high fat chow feeding. While female and male βNr4a1−/− mice were no different than wild type controls when fed a standard chow diet, a clear sex dependent difference is observed when fed a high fat diet. While high fat fed male βNr4a1−/− have improved fasting and non-fasting blood glucose levels and no change in glucose tolerance, high fat fed female βNr4a1−/− mice have impaired glucose tolerance as early as one month after beginning high fat feeding. We also found that βNr4a1−/− female mice have decreased β-cell mass and decreased expression in known targets of Nr4a1 regulation including Eno1 and SDHβ. Our data suggest that Nr4a1 is critical for maintenance of beta cell function, and that loss of Nr4a1 under conditions of obesity and overnutrition in females results in impaired beta cell compensation and function. NIH R15DK124835-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ectopic Lipid Accumulation Correlates with Cellular Stress in Rabbit Blastocysts from Diabetic Mothers.

Maternal diabetes mellitus in early pregnancy leads to hyperlipidemia in reproductive tract organs and an altered embryonic environment. To investigate the consequences on embryonic metabolism, the effect of high environmental-lipid levels was studied in rabbit blastocysts cultured with a lipid mixture in vitro and in blastocysts from diabetic, hyperlipidemic rabbits in vivo. The gene and protein expression of marker molecules involved in lipid metabolism and stress response were analyzed. In diabetic rabbits, the expression of embryoblast genes encoding carnitine palmityl transferase 1 and peroxisome proliferator-activated receptors α and γ increased, whereas trophoblast genes encoding for proteins associated with fatty acid synthesis and β-oxidation decreased. Markers for endoplasmic (activating transcription factor 4) and oxidative stress (nuclear factor erythroid 2-related factor 2) were increased in embryoblasts, while markers for cellular redox status (superoxide dismutase 2) and stress (heat shock protein 70) were increased in trophoblasts from diabetic rabbits. The observed regulation pattern in vivo was consistent with an adaptation response to the hyperlipidemic environment, suggesting that maternal lipids have an impact on the intracellular metabolism of the preimplantation embryo in diabetic pregnancy and that embryoblasts are particularly vulnerable to metabolic stress.

295-LB: Pancreatic Peroxisomes Are Required for Physiological Regulation of Insulin Secretion and Maintenance of Normal Glucose Tolerance in Male Mice

The regulation of glucose-stimulated insulin secretion (GSIS) is central to maintenance of glucose disposal. The role of lipid storage and lipid oxidation to regulate pancreatic islet β-cell insulin secretion is not completely understood. Peroxisomes are enriched in insulin-producing β-cells, but their contribution to β-cell function and maturity is lacking. Therefore, we generated a novel model of peroxisomal dysfunction to test the hypothesis that peroxisomal lipid metabolism is required to prevent a hyperlipidemic environment that interferes with β-cell function and maturity. Pex5 plays a critical role in importing the majority of peroxisomal proteins into the peroxisomal matrix; thus, deletion of the Pex5 gene creates a cellular environment with reductions in function of this organelle. In this study, we bred Pex5 mice on a C57BL/6J background containing ‘floxed’ alleles to Pdx1-cre mice to generate offspring with a pancreas-wide deficiency in Pex5 expression and abundance. Glucose tolerance was impaired by 12 weeks in male mice (n=20; AUC p<0.05). Surprisingly, GSIS was elevated in Pex5Pdx1-/- mice compared to littermate controls both in vivo (n=15; AUC p<0.05) and ex vivo in isolated islets as measured by perifusion analysis (n=12; AUC p<0.01). We further found that a subset of β-cells from Pex5Pdx1-/- mice expressed the de-differentiation marker Aldh1a3, while a subset of β-cells showed reductions in MafA and Nkx6.1 staining compared to controls. Perilipin-1 staining showed increased presence of lipid droplets in pancreatic tissue of Pex5Pdx1-/- mice versus controls. Thus, pancreatic deletion of peroxisomal function results in increased lipid storage in pancreatic tissue that is correlated with exaggerated insulin secretion. Collectively, these data are in support of a model whereby peroxisomal function supports β-cell insulin secretion and maintenance of the fully differentiated state. Disclosure S. Burke: None. S. Ghosh: None. D. Burk: None. R. Noland: None. J. Collier: None.

Effects of Hyperlipidemia on Osseointegration of Dental Implants and Its Strategies

Hyperlipidemia refers to the abnormal increase in plasma lipid level exceeding the normal range. At present, a large number of patients require dental implantation. However, hyperlipidemia affects bone metabolism, promotes bone loss, and inhibits the osseointegration of dental implants through the mutual regulation of adipocytes, osteoblasts, and osteoclasts. This review summarized the effects of hyperlipidemia on dental implants and addressed the potential strategies of dental implants to promote osseointegration in a hyperlipidemic environment and to improve the success rate of dental implants in patients with hyperlipidemia. We summarized topical drug delivery methods to solve the interference of hyperlipidemia in osseointegration, which were local drug injection, implant surface modification and bone-grafting material modification. Statins are the most effective drugs in the treatment of hyperlipidemia, and they also encourage bone formation. Statins have been used in these three methods and have been found to be positive in promoting osseointegration. Directly coating simvastatin on the rough surface of the implant can effectively promote osseointegration of the implant in a hyperlipidemic environment. However, the delivery method of this drug is not efficient. Recently, a variety of efficient methods of simvastatin delivery, such as hydrogels and nanoparticles, have been developed to boost bone formation, but few of them were applied to dental implants. Applicating these drug delivery systems using the three aforementioned ways, according to the mechanical and biological properties of materials, could be promising ways to promote osseointegration under hyperlipidemic conditions. However, more research is needed to confirm.

1446-P: Sex-Specific Effects of Nr4a1 in the Pancreatic Beta Cell

A central aspect of type 2 diabetes disease progression is impaired functional β-cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the β-cell. Nr4a1 expression is decreased in the β-cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetics. Here we demonstrate sex specific effects of β-cell specific Nr4a1 deletion under high fat chow feeding. While female and male βNr4a1-/- mice were no different than wild type controls when fed a standard chow diet, a clear sex dependent difference is observed when fed a high fat diet. High fat fed male βNr4a1-/- have improved fasting and non-fasting blood glucose levels, high fat fed female βNr4a1-/- mice have impaired glucose tolerance as early as two months after beginning high fat feeding. Furthermore, female βNr4a1-/- mice have decreased β-cell mass and improved insulin tolerance. Given the sex specific differences in glucose tolerance, we demonstrated that female mice fed a high fat diet have increased circulating estrogen, and that treatment of INS-1 832/13 cells and primary mouse islets with estradiol resulted in increased expression of Nr4a1 and not the other two Nr4a family members. Our data suggest that Nr4a1 is critical for estrogen mediated maintenance of beta cell function and mass under obesogenic conditions, and that loss of Nr4a1 under conditions of obesity and overnutrition in females results in impaired beta cell compensation and function. Disclosure J.S.Tessem: None. J.Herring: None. Funding National Institutes of Health (1R15DK124835-01A1)

Looking at the Future Through the Mother’s Womb: Gestational Diabetes and Offspring Fertility

Altered nutrition or intrauterine exposure to various adverse conditions during fetal development or earlier in a mother's life can lead to epigenetic changes in fetal tissues, predisposing those tissues to diseases that manifest when offspring become adults. An example is a maternal obesity associated with gestational diabetes (GDM), where fetal exposure to a hyperglycemic, hyperinsulinemic, and/or hyperlipidemic gestational environment can provoke epigenetic changes that predispose offspring to various diseased conditions later in life. While it is now well established that offspring exposed to GDM have an increased risk of developing obesity, metabolic disorders, and/or cardiovascular disease in adult life, there are limited studies assessing the reproductive health of these offspring. This mini-review discusses the long-term effect of in utero exposure to GDM-associated adverse prenatal environment on the reproductive health of the offspring. Moreover, using evidence from various animal models and human epidemiological studies, this review offers molecular insight and understanding of how epigenetic reprogramming of genes culminates in reproductive dysfunction and the development of subfertility or infertility later in adult life.

Mild hyperlipidemia in mice aggravates platelet responsiveness in thrombus formation and exploration of platelet proteome and lipidome

Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe−/− and Ldlr−/− mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe−/− mice). Bone marrow from wild-type or Ldlr−/− mice was transplanted into irradiated Ldlr−/− recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe−/− and Ldlr−/− mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype.

Desmosterol, an intermediate of cholesterol biosynthesis, modulates B cell activation and functions

Abstract Introduction Atherosclerosis is a disease of large/medium size vessels attributed to a hyperlipidemic environment and a low-grade chronic inflammation. Normally, macrophages uptake modified low-density lipoprotein (mLDL), resulting in excess intracellular desmosterol, an immediate precursor to cholesterol, which promotes anti-inflammatory signaling. In contrast, mLDL uptake by macrophages in atherosclerosis produces foam cells that play an atherogenic role. While it has been previously shown that B cells can uptake mLDL, it remains unclear how mLDL uptake modulates B cell phenotype. Methods Murine B cells were treated with 1 mM of desmosterol for 12/24 hrs, cholesterol efflux genes were analyzed using qPCR. CFSE-labeled splenocytes were incubated with LPS/BAFF, treated with 1 mM of desmosterol for 72 hrs, and analyzed via FACS. B cells isolated from transgenic mice ooverexpressing DHCR24, a dehydrocholesterol reductase, were analyzed for desmosterol content by lipidomics, Ca2+ flux by FACS, and DNP-Ficoll induced Igs production in vivo by ELISA. Results Desmosterol uptake results in an increased expression of cholesterol efflux genes and attenuated B cell proliferation. Overexpression of DHCR24 leads to a decreased intracellular desmosterol, hyper-response of B cells shown by increased Ca2+. DNP-Ficoll immunization of B cell-deficient mice populated with either DHCR24- or WT B cells induce more anti-IGM specific Abs in the DHCR24-B cell recipients. Conclusions These results suggest desmosterol is synthesized and sensed by B cells, and its accumulation regulates B cell activation thresholds in vitro and in vivo. These novel data offer new insights for B cell biology and atherosclerosis pathology.

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease.

Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.

Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells.

To investigate the prevention of cardiac remodelling and inflammatory immune response after myocardial infarction (MI) via ACEI regulating dendritic cells (DCs), we explored whether the protective effect of ACEI was repressed under hyperlipidemic environment. In vivo, the survival rate and left ventricular function of the mice were recorded on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were assessed for Ang II concentration, inflammatory cytokines and DCs expression. In vitro, DCs were treated with ox‐LDL + Ang II, simulating the internal environment of MI in ApoE−/− mice to explore the mechanism involved in the DCs maturation and inflammation. Under hyperlipidemic circumstances, we found that the cardioprotective effect of ACEI was attenuated through regulating DCs maturation and inflammation after MI, affecting survival rate and left ventricular function. Effects of lisinopril on the release of spleen‐derived DCs and myocardial infiltration were also reduced under hyperlipidemic conditions. In vitro, immune maturation and inflammation of DCs were further induced by ox‐LDL on the basis of Ang II treatment, as indicated by the upregulation of CD83, CD86, and the expressions of cytokines and chemokines. Furthermore, ox‐LDL could activate TLR4‐MyD88 signalling pathway, promoting IRAK‐4 and NF‐κB. The present study demonstrated that ACEI reduced the recruitment of DCs to the infarct site, leading to a higher survival rate and improved function. However, this effect was inhibited under hyperlipidemic environment. TLR4‐MyD88 signalling pathway may be responsible for the molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox‐LDL.

Cellular and Molecular Links between Autoimmunity and Lipid Metabolism.

The incidence of atherosclerosis is higher among patients with several autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is well documented that innate immune cells including macrophages and dendritic cells sense lipid species such as saturated fatty acids and oxidized low-density lipoprotein and produce pro-inflammatory cytokines and chemokines. However, whether a hyperlipidemic environment also impacts autoimmune T cell responses has been unclear. Among CD4+ T cells, Th17 and follicular helper T (Tfh) cells are known to play pathogenic roles in the development of hyperlipidemia-associated autoimmune diseases. This review gives an overview of the cellular and molecular mechanisms by which dysregulated lipid metabolism impacts the pathogenesis of autoimmune diseases, with specific emphasis on Th17 and Tfh cells.

Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo

AbstractDyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction–induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer exposure and, subsequently, recruitment of the prothrombinase complex, resulting in the generation of fibrin from the activation of thrombin. Caspase activity was observed when platelets were stimulated with oxLDL. This was prevented by inhibiting CD36 and ERK5. Furthermore, oxLDL potentiates convulxin/glycoprotein VI–mediated fibrin formation by platelets, which was prevented when CD36, ERK5, and caspases were inhibited. Using 2 in vivo arterial thrombosis models in apoE-null hyperlipidemic mice demonstrated enhanced arterial fibrin accumulation upon vessel injury. Importantly, absence of ERK5 in platelets or mice lacking CD36 displayed decreased fibrin accumulation in high-fat diet–fed conditions comparable to that seen in chow diet–fed animals. These findings suggest that platelet signaling through CD36 and ERK5 induces a procoagulant phenotype in the hyperlipidemic environment by enhancing caspase-mediated PSer exposure.

P 225 - Impact of lipotoxic stress on proteolytic systems in human liver cells

Type 2 diabetes is a chronic metabolic disorder characterized, among other features, by elevated levels of circulatory free fatty acids. Several studies in animal and cellular models indicate that increased accumulation of lipids leads to oxidative and ER stress, mitochondrial dysfunction and alteration of proteostasis, resulting in cellular dysfunction. Proteostasis is mainly regulated by two pathways, the “ubiquitin-proteasome system” and the “autophagy-lysosomal system”. The proteolytic systems degrade un-/misfolded proteins and regulate the functional protein pool. However, it remains elusive if a hyperlipidemic environment leads to cellular dysfunction via alterations of both proteolytic systems. The purpose of this study is to investigate the role of the proteolytic systems in lipotoxic conditions. Therefore, we induced lipid accumulation in HepG2 cells by exposing them to palmitic acid. According to preliminary data palmitic acid induced lipid droplet formation and alters the cellular redox state, iNOS levels and induces ER stress. Under these conditions, further experiments are being performed to elucidate the impact of lipotoxic stress on the proteolytic systems in HepG2 cells.

ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model.

BackgroundThe risk for developing cardiovascular disease is greater in patients with rheumatoid arthritis (RA) than in the general population. While patients with RA also have dyslipidemia, the impact of dyslipidemia on the severity of inflammatory arthritis and associated cardiovascular disease is unclear. Currently, there are conflicting results regarding arthritis incidence in apolipoprotein E (ApoE) deficient mice, which spontaneously exhibit both hyperlipidemia and atherosclerosis. Here, we utilize a distinct approach to investigate the contribution of a hyperlipidemic environment on the development of arthritis and atherosclerosis in mice lacking ApoE.MethodsK/BxN serum transfer-induced arthritis (STIA) was assessed in C57BL/6 (control) and ApoE−/− mice using clinical indices and immunohistochemical staining. Ankle synoviums were processed for flow cytometry. Aortic atherosclerosis was quantitated using Sudan IV staining. Serum cholesterol and cytokine levels were determined via enzymatic and luminex bead-based assays, respectively.ResultsApoE−/− mice developed a sustained and enhanced semi-chronic inflammatory arthritis as compared to control mice. ApoE−/− mice had increased numbers of foamy macrophages, enhanced joint inflammation and amplified collagen deposition versus controls. The presence of arthritis did not exacerbate serum cholesterol levels or significantly augment the level of atherosclerosis in ApoE−/− mice. However, arthritic ApoE−/− mice exhibited a marked elevation of IL-6 as compared to non-arthritic ApoE−/− mice and arthritic C57BL/6 mice.ConclusionsLoss of ApoE potentiates a semi-chronic inflammatory arthritis. This heightened inflammatory response was associated with an increase in circulating IL-6 and in the number of foamy macrophages within the joint. Moreover, the foamy macrophages within the arthritic joint are reminiscent of those within unstable atherosclerotic lesions and suggest a pathologic role for foamy macrophages in propagating arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0912-y) contains supplementary material, which is available to authorized users.

Atherosclerosis: the interplay between lipids and immune cells.

Cardiovascular disease is the leading cause of mortality worldwide. The underlying cause of the majority of cardiovascular disease is atherosclerosis. In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall. However, today's picture of the pathogenesis of atherosclerosis is much more complex, with a key role for immune cells and inflammation in conjunction with hyperlipidemia, especially elevated (modified) LDL levels. Knowledge on immune cells and immune responses in atherosclerosis has progressed tremendously over the past decades, and the same is true for the role of lipid metabolism and the different lipid components. However, it is largely unknown how lipids and the immune system interact. In this review, we will describe the effect of lipids on immune cell development and function, and the effects of immune cells on lipid metabolism. Recently, novel data have emerged that show that immune cells are affected, and behave differently in a hyperlipidemic environment. Moreover, immune cells have reported to be able to affect lipid metabolism. In this review, we will summarize the latest findings on the interactions between lipids and the immune system, and we will discuss the potential consequences of these novel insights for future therapies for atherosclerosis.

Interleukin‐19 Can Simultaneously Reduce Atherosclerosis and Increase Perfusion in Hind Limb Ligated LDLr−/− Mice

Peripheral arterial disease is often a co‐morbidity with hypercholesterolemia and atherosclerosis. We have previously characterized Interleukin‐19 (IL‐19) as an anti‐inflammatory, Th2 cytokine. Past studies in our lab have determined that IL‐19 can decrease atherosclerosis in LDLr−/− mice and increase angiogenesis in the hind limb ischemia (HLI) model, suggesting that IL‐19 has both anti‐atherosclerotic and pro‐angiogenic effects.ObjectiveThe purpose of this study was to determine whether IL‐19 can induce angiogenesis within the background of hyperlipidemia and atherosclerosis and potentially reduce atherosclerosis and induce angiogenesis simultaneously.Methods and ResultsWe utilized three different, yet complementary platforms to test this hypothesis. We fed LDLr−/− mice high fat diet (HFD) for 12 weeks, then performed HLI surgery and continued HFD and treatment with rIL‐19 (10ng/g/day) or PBS intraperitoneal (IP) injections for an additional 4 weeks. Doppler imaging revealed increased perfusion in mice treated with IL‐19 when compared to PBS controls. Additional en face evaluation of the aortic arches of these mice demonstrated a trend toward decreased plaque burden in the IL‐19 treated mice, though it was not statistically significant. These data suggest that IL‐19 is capable of promoting angiogenesis, even in a hyperlipidemic environment. We used this same experimental model, but instead treated LDLr−/− mice with IL‐19 (10ng/g/day) or PBS by daily IP injection throughout the initial 12 weeks of HFD, in addition to four weeks following HLI surgery. Doppler imaging demonstrated increased perfusion in IL‐19 treated mice when compared to PBS controls, and en face evaluation showed decreased plaque burden in the IL‐19 treated mice, supporting our hypothesis that IL‐19 is capable of simultaneously decreasing atherosclerosis and promoting angiogenesis in the background of hyperlipidemia. Finally, we hypothesized that lack of IL‐19 would both reduce perfusion and exacerbate atherosclerosis. We generated a double knockout mouse model (dKO) by crossing the LDLr−/− with an IL‐19−/− mouse. We placed dKO and LDLr−/− mice on HFD for 12 weeks, completed HLI and performed Doppler imaging for 4 weeks. Preliminary results suggest dKO mice demonstrate both decreased perfusion and increased plaque burden.ConclusionsThe current dogma referred to as the Janus phenomenon suggests that pro‐angiogenic cytokines are also pro‐atherosclerotic. Collectively, these data suggest IL‐19 is the only cytokine to date that challenges this theory, demonstrating both pro‐angiogenic and anti‐atherosclerotic effects.Support or Funding InformationThis work was supported by grants HL115575 and HL117724 from the National Heart Lung, and Blood Institute of the National Institutes of Health, and Grant 13GRNT1685003 from the American Heart Association to MVA.

Developmental Programming of Pediatric Nonalcoholic Fatty Liver Disease

The incidence of pediatric nonalcoholic fatty liver disease has increased dramatically, and growing evidence indicates that the pathophysiology may be unique from the adult form, suggesting a role for early-life events. Recent radiologic techniques have now demonstrated that maternal obesity contributes to hepatic fat storage in newborn infants. In this review, we will explore how maternal obesity and a hyperlipidemic environment can initiate liver histopathogenesis in utero, including steatosis, mitochondrial dysfunction, oxidative stress, and inflammatory priming. Thus, early exposure to excess lipids may represent the "first hit" for the fetal liver, placing it on a trajectory toward future metabolic disease.