Systemic Lipid Metabolism Research Articles

FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells.

FGF21, a member of the fibroblast growth factor superfamily, is an important endogenous regulator of systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. However, whether FGF21 is associated with atherosclerotic diseases remains unclear. In this study, the effects of FGF21 on cholesterol efflux in THP1 macrophage-derived foam cells and the underlying mechanisms were investigated. THP1 macrophage-derived foam cells were incubated with 0, 25, 50, 100, 200, and 400 ng/mL of FGF21 for varying time periods (0, 6, 12, and 24 h). Cholesterol efflux onto apoA-1 was assessed by high-performance liquid chromatography assays, while change in ABCA1 expression was analyzed by western blot and real-time quantitative PCR. Incubation was performed with the ERK1/2-specific inhibitor PD98059, PPARγ-specific inhibitor GW9662, and LXRα siRNA. Our results show that FGF21 promotes cholesterol efflux and ABCA1 expression in THP1 macrophage-derived foam cells in a dose- and time-dependent manner. In addition, inhibition of ERK1/2 or PPARγ, or knockdown of LXRα attenuated FGF21-mediated promotion of ABCA1 expression and cholesterol efflux. These results demonstrate that FGF21 can promote cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells.

Deficiency of CCAAT/Enhancer Binding Protein-Epsilon Reduces Atherosclerotic Lesions in LDLR−/− Mice

The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBPε is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (Ldlr−/−) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated Ldlr and Cebpe double-knockout (llee) mice and compared their atherogenic phenotypes to Ldlr single deficient (llEE) mice after HCD. Macrophages from llee mice have reduced lipid uptake by foam cells and impaired phagokinetic motility in vitro compared to macrophages from llEE mice. Also, compared to llEE mice, llee mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of llee male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBPε is involved in systemic lipid metabolism and that silencing of C/EBPε could decrease the development of atherosclerosis.

Monounsaturated fatty acids in serum triacylglycerols are associated with response to neoadjuvant chemotherapy in breast cancer patients

Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.

System lipidic distress-syndrome at traumatic illness

The purpose of work was studying of a role of systemic lipid metabolism disturbances in a pathogenesis of homeostasis disorders in the early posttraumatic period at fractures of pelvic bones in experiment and clinic. Pilot and clinical studies are put in a basis of work with application of the techniques estimating structure phospholipid membranes of erythrocytes, cells of a liver, kidneys, heart, lungs, and also intensity of the processes participating in a regulation of a lipid metabolism. Results. It is established that at a pelvic trauma change of lipids structure arise not only in a blood, but also other tissues structures (a liver, kidneys, lungs, heart) that is caused by activization of phosfolipaze systems, an intensification of lipids peroxidation process. There is a systemic lipid distress syndrome. The arisen changes - one of significant in a pathogenesis of traumatic illness. At modification of lipid structure of a biomembrane the morphological and functional condition of a cell starts suffering. It is substrate of emergence of disregulation pathologies. The received scientific facts can be the base for intelligent medical actions for the purpose of the prevention of emergence of a "favorable" background of disregulation conditions by vectorial impact on one of its main pathogenetic links - a systemic lipide distress syndrome.

Oral retinoids and plasma lipids

Retinoids and rexinoids are prescribed for conditions ranging from acne vulgaris to hyperkeratosis to cutaneous T cell lymphoma. Dyslipidemia is a frequent consequence of the use of these drugs, with more than one-third of patients manifesting aberrations in triglyceride (TG) levels. The efficacy of retinoic acid derivatives is linked to their influence on lipid metabolism in the skin, which can impair systemic lipid trafficking and metabolism in some patients. Thus, baseline screening for preexisting dyslipidemia and regular follow-up lipid panels are mandated, especially when powerful agents such as bexarotene are used. Dietary modification, increased physical activity, and weight management are the cornerstones of initial management for mild hypertriglyceridemia, which is a contributor to cardiovascular risk. More severe impairments (fasting TG > 500 mg/dL) warrant pharmacologic interventions early on to reduce the risk of pancreatitis. Retinoic acid derivative action, lipid metabolism, and treatment of incident dyslipidemias are reviewed to empower prescribers in management of adverse lipid effects.

T Cell-based Therapies for Atherosclerosis

Cardiovascular diseases (CVDs), largely due to atherosclerosis, are the major causes of death in today's world. Atherosclerosis is a chronic inflammatory condition initiated by retention and accumulation of cholesterol-containing lipoproteins, in particular low-density lipoprotein (LDL), in the artery wall. This initiates pathological responses of immune cells that lead to atherosclerotic plaque formation. T cells are present during all stages of the disease, and play an essential role in the initiation and progression of plaques. Whereas most T effector cell responses have been suggested to aggravate atherosclerosis, regulatory T cells (Tregs) have been shown to limit inflammation and inhibit the formation of lesions. In addition to their effects on the local pathological process, T cells and their released mediators modulate systemic lipid metabolism and can increase risk of CVDs. Such knowledge on the pathological and protective function of these cells has led to significant advances in the field. This review examines experimental and pre-clinical studies approaching the manipulation of cellular immunity in atherosclerosis. Modulation of T cells responses by vaccination, antibody therapies, dendritic cell based-therapies, and using amino acid-derived metabolites have shown benefits against atherosclerotic plaque progression in animal models. The clinical benefit of T cell-based therapies in humans still requires further investigation.

SAT0351 Adipokines as New Laboratory Markers in Osteoarthritis

BackgroundThere is some data that osteoarthritis (OA) may be part of systemic lipid metabolism disorder. Some authors suppose that fat tissue may be origin of biologically active substances such as...

Cardiovascular Effects of Pulmonary Exposure to Titanium Dioxide Nanoparticles in ApoE Knockout Mice

Existing studies on the inhalation toxicology of titanium dioxide (TiO2) have focused on possible carcinogenic capacity; however researches on the cardiovascular effect are limited, particularly in terms of susceptible animal models. The present study examined the inhalation toxicology of nano-TiO2 in ApoE knockout mice (ApoE-/- mice), an atherosclerosis susceptible animal model. The nano-TiO2 particles used were anatase type and the diameter ranged from 5 to 10 nm. ApoE-/- mice were randomly divided into five groups (high dose group, median dose group, low dose group, PBS vehicle control group and the nontreatment control group), each of which were given tracheal instillation of nano-TiO2 at the dose of 100 microg, 50 microg and 10 microg and PBS solution per week respectively, totally for six weeks, while the nontreatment control group received no tracheal instillation. We measured various indicators of inflammation, endothelial dysfunction and lipid metabolism in serum, and determined plaque formation on the aorta. After six weeks of treatment, there was significant difference between the high dose group and PBS control group in terms of C reactive protein (CRP), nitric oxide (NO), endothelial nitric oxide synthases (eNOS), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) in serum. The results also showed ratio of plaque area to luminal area and the ratio of the lipid-rich core area to plaque area in the median and high nano-TiO2 dose group significantly increased respectively in HE stained cross-sections. Our study showed that tracheal instillation of nano-TiO2 particles induced considerable systemic inflammation, endothelial dysfunction and lipid metabolism dysfunction, contributing to the progression of atherosclerosis.

Fibroblast Growth Factor-19 Action in the Brain Reduces Food Intake and Body Weight and Improves Glucose Tolerance in Male Rats

Fibroblast growth factor-19 (FGF19) and its rodent ortholog, FGF15, are hormones produced in the distal small intestine and secreted into the circulation after a meal. In addition to controlling the enterohepatic circulation of bile acids, FGF15/19 also regulates systemic lipid and glucose metabolism. In these experiments we investigated the hypothesis that, like other gut-derived postprandial hormones, FGF15/19 can act in the central nervous system to elicit its metabolic effects. We found that FGF-receptors 1 and 4 are present in rat hypothalamus, and that their expression was reduced by up to 60% in high-fat fed rats relative to lean controls. Consistent with a potential role for brain FGF15/19 signaling to regulate energy and glucose homeostasis, and with a previous report that intracerebroventricular (i.c.v.) administration of FGF19 increases energy expenditure, we report that acute i.c.v. FGF19 reduces 24-h food intake and body weight, and acutely improves glucose tolerance. Conversely, i.c.v. administration of an FGF-receptor inhibitor increases food intake and impairs glucose tolerance, suggesting a physiological role for brain FGF receptor signaling. Together, these findings identify the central nervous system as a potentially important target for the beneficial effects of FGF19 in the treatment of obesity and diabetes.

Cinnamon polyphenols regulate multiple metabolic pathways involved in insulin signaling and intestinal lipoprotein metabolism of small intestinal enterocytes

ObjectiveIncreasing evidence suggests that dietary factors may affect the expression of multiple genes and signaling pathways, which regulate intestinal lipoprotein metabolism. The small intestine is actively involved in the regulation of dietary lipid absorption, intracellular transport, and metabolism and is closely linked to systemic lipid metabolism. Cinnamon polyphenols have been shown to improve glucose, insulin, and lipid metabolism and improve inflammation in cell culture, animal, and human studies. However, little is known of the effects of an aqueous cinnamon extract (CE) on the regulation of genes and signaling pathways related to intestinal metabolism. The aim of the study was to investigate the effects of a CE on the primary enterocytes of chow-fed rats. MethodsFreshly isolated intestinal enterocytes were used to investigate apolipoprotein-B48 secretion by immunoprecipitation; gene expressions by quantitative reverse transcriptase-polymerase chain reaction and the protein and phosphorylation levels were evaluated by western blot and flow cytometric analyses. ResultsEx vivo, the CE significantly decreased the amount of apolipoprotein-B48 secretion into the media, inhibited the mRNA expression of genes of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, and induced the expression of the anti-inflammatory gene, Zfp36. CE also increased the mRNA expression of genes leading to increased insulin sensitivity, including Ir, Irs1, Irs2, Pi3k, and Akt1, and decreased Pten expression. CE also inhibited genes associated with increased cholesterol, triacylglycerols, and apolipoprotein-B48 levels, including Abcg5, Npc1l1, Cd36, Mttp, and Srebp1c, and facilitated Abca1 expression. CE also stimulated the phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular-signal-regulated kinase expressions determined by flow cytometry, with no changes in protein levels. ConclusionsThese results demonstrate that the CE regulates genes associated with insulin sensitivity, inflammation, and cholesterol/lipogenesis metabolism and the activity of the mitogen-activated protein kinase signal pathway in intestinal lipoprotein metabolism.

Central leptin and insulin administration modulates serum cytokine- and lipoprotein-related markers

In most obese patients there is an inflammatory state characterized by lipid abnormalities, hyperleptinemia and hyperinsulinemia. ObjectiveThe objective was to identify mechanisms involved in leptin's role in the attenuation of the response to insulin using a proteomic approach. Material/MethodsWe studied the serum proteomic profile of rats treated by central leptin infusion followed by an injection of insulin. We analyzed the relationship between these proteins and serum cytokine and apolipoprotein levels. ResultsOut of 81 protein spots, intensity differences were found in 11, corresponding to 5 proteins: three isoforms of α1 macroglobulin; three of haptoglobin and serum amyloid P component-precursor. All of these are acute-phase proteins involved in inflammation and are correlated with cytokine levels. Additionally, two apolipoprotein E and two apolipoprotein A1 isoforms were identified and were found to correlate with LDL and HDL. ConclusionsOur results indicate that increased leptin and insulin levels change these circulating proteins, thus promoting systemic inflammation and changing lipid metabolism.

Characterization of the cytokine expression profiles of the aorta and liver of young tumor necrosis factor alpha mutant mice

Both the aorta and the liver are major organs that play important roles in lipid metabolism, and they are subject to systemic as well as local inflammatory responses in metabolic syndrome. Our previous study indicated that TNFα deficiency influences atherogenesis by reducing inflammation of the aorta. To better understand this phenomenon, the mRNA and protein expression profiles of a panel of cytokines in the aorta and liver of young TNFα-null (TNFα(-/-)) mice were analyzed and compared with age- and gender-matched wild-type (WT) control mice. In the aorta, IL-2 and GM-CSF were up-regulated versus WT mice, while IL-1β, IL-4, IL-6, IL-10, MCP-1, IFN-γ, and the adhesion molecules ICAM-1 and VCAM-1 were down-regulated. In the liver, however, the expressions of NF-κB, IL-1, IL-2, IL-6, IL-10, ICAM-1, and VCAM-1 were significantly up-regulated in TNFα(-/-) mice, while IFN-γ and IL-4 were down-regulated. Out of the 62 cytokines analyzed, 22 in the aorta and 27 in the liver were altered by 2-fivefolds at the protein level in TNFα(-/-) mice. Our data demonstrated that the loss of TNFα function led to various changes in the levels of cytokine expression in these organs at both the transcriptional and translational levels. These results indicated that the changes in cytokine expression patterns in the aorta and the liver may further influence the progression of systemic or local lipid metabolism dysregulation and pathogenesis in animals with TNFα dysfunction representing inflammation-related diseases, such as atherosclerosis and metabolic syndrome.

Alterations in Lipid Metabolism Mediate Inflammation, Fibrosis, and Proliferation in a Mouse Model of Chronic Cholestatic Liver Injury

The liver controls central processes of lipid and bile acid homeostasis. We aimed to investigate whether alterations in lipid metabolism contribute to the pathogenesis of chronic cholestatic liver disease in mice. We used microarray and metabolic profiling analyses to identify alterations in systemic and hepatic lipid metabolism in mice with disruption of the gene ATP-binding cassette sub-family B member 4 (Abcb4(-/-) mice), a model of inflammation-induced cholestatic liver injury, fibrosis, and cancer. Alterations in Abcb4(-/-) mice, compared with wild-type mice, included deregulation of genes that control lipid synthesis, storage, and oxidation; decreased serum levels of cholesterol and phospholipids; and reduced hepatic long-chain fatty acyl-CoAs (LCA-CoA). Feeding Abcb4(-/-) mice the side chain-modified bile acid 24-norursodeoxycholic acid (norUDCA) reversed their liver injury and fibrosis, increased serum levels of lipids, lowered phospholipase and triglyceride hydrolase activities, and restored hepatic LCA-CoA and triglyceride levels. Additional genetic and nutritional studies indicated that lipid metabolism contributed to chronic cholestatic liver injury; crossing peroxisome proliferator-activated receptor (PPAR)-α-deficient mice with Abcb4(-/-) mice (to create double knockouts) or placing Abcb4(-/-) mice on a high-fat diet protected against liver injury, with features similar to those involved in the response to norUDCA. Placing pregnant Abcb4(-/-) mice on high-fat diets prevented liver injury in their offspring. However, fenofibrate, an activator of PPARα, aggravated liver injury in Abcb4(-/-) mice. Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease in mice.

Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells

It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin+/+ and Parkin-/- mice to a high-fat and -cholesterol diet (HFD). Parkin-/- mice resisted weight gain, steatohepatitis, and insulin resistance. In wild-type mice, the HFD markedly increased hepatic Parkin levels in parallel with lipid transport proteins, including CD36, Sr-B1, and FABP. These lipid transport proteins were not induced in Parkin-/- mice. The role of Parkin in fat uptake was confirmed by increased oleate accumulation in hepatocytes overexpressing Parkin and decreased uptake in Parkin-/- mouse embryonic fibroblasts and patient cells harboring complex heterozygous mutations in the Parkin-encoding gene PARK2. Parkin conferred this effect, in part, via ubiquitin-mediated stabilization of the lipid transporter CD36. Reconstitution of Parkin restored hepatic fat uptake and CD36 levels in Parkin-/- mice, and Parkin augmented fat accumulation during adipocyte differentiation. These results demonstrate that Parkin is regulated in a lipid-dependent manner and modulates systemic fat uptake via ubiquitin ligase-dependent effects. Whether this metabolic regulation contributes to premature Parkinsonism warrants investigation.

Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis

Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1c mediated the insulin and liver X receptor agonist TO901317-dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased the serum triglyceride level and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance. Our data suggest that mouse PNPLA3, which is a lipogenic gene directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism.

Association of Lipid Metabolism with Ovarian Cancer

Defects in lipid metabolism have been found to be linked to several diseases, among which atherosclerosis, hypertension, obesity, and diabetes are the most important. Although cancer is chiefly a genetic disease, dietary lipid intake and metabolism are related to some cancer risks, including the risk for ovarian cancer. Higher intake of dietary lipids, systemic lipid metabolism malfunction, and abnormal serum lipid levels are somehow related to ovarian cancer. Overexpression of some lipid metabolic enzymes are also found in ovarian cancer. In this review article, we summarize the relationships between lipid intake, lipid metabolism, and ovarian cancer.

Novel roles for JNK1 in metabolism

Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies. Here, c-Jun N-terminal Kinase (JNK) 1 knockout mice have been shown to exhibit protection from diet-induced obesity, glucose intolerance, and insulin resistance. Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far. Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.

FABP4: a novel candidate gene for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder involving a number of genetic and environmental factors. Adipocyte-fatty acid-binding protein (FABP4) is an adipokine regulating systemic insulin sensitivity, lipid and glucose metabolism. In humans serum FABP4 levels correlate significantly with features of PCOS. Previous researches showed strong evidences that FABP4 impacted the developing of PCOS possibly through its protein alteration or transcription regulation. Thus, the present study is the first attempt to identify the possible genetic role of FABP4 gene in the development of PCOS. About 1000 bp of the promoter region and four exons of FABP4 gene of 178 PCOS patients and 171 healthy controls were directly sequenced. Three polymorphisms, rs16909225, rs3834363, and rs16909220, were identified, of which rs16909225 and rs16909220 were completely linked (r² = 1) and not associated with the development of PCOS, while the -2-bp/-2-bp genotype of rs3834363 was significantly higher in PCOS than in the controls (χ² = 7.39, df = 1, P = 0.007, OR = 1.80 95% CI: 1.18-2.75). The present study is the first to establish an association between FABP4 gene polymorphisms and the development of PCOS.

The outer frontier: the importance of lipid metabolism in the skin

The skin serves the vital function of providing a barrier between the hostile external environment and the host. While the skin has many important barrier functions, the two that are absolutely essential for survival are the barrier to the movement of water and electrolytes (permeability barrier) and the barrier against invasive and toxic microorganisms (antimicrobial barrier). Lipids play an essential role in the formation and maintenance of both the permeability and antimicrobial barriers. A hydrophobic extracellular lipid matrix in the stratum corneum composed primarily of ceramides, cholesterol, and free fatty acids provides the barrier to the movement of water and electrolytes. A variety of lipids, such as fatty alcohols, monoglycerides, sphingolipids, phospholipids, and in particular free fatty acids, have antimicrobial activity and contribute to the antimicrobial barrier. In addition to these essential functions, we will also review the ability of skin surface cholesterol to reflect alterations in systemic lipid metabolism and the risk of atherosclerosis.

Identification of MUP1 as a Regulator for Glucose and Lipid Metabolism in Mice

Major urinary protein (MUP) 1 is a lipocalin family member abundantly secreted into the circulation by the liver. MUP1 binds to lipophilic pheromones and is excreted in urine. Urinary MUP1/pheromone complexes mediate chemical communication in rodents. However, it is unclear whether circulatory MUP1 has additional physiological functions. Here we show that MUP1 regulates glucose and lipid metabolism. MUP1 expression was markedly reduced in both genetic and dietary fat-induced obesity and diabetes. Mice were infected with MUP1 adenoviruses via tail vein injection, and recombinant MUP1 was overexpressed in the liver and secreted into the bloodstream. Recombinant MUP1 markedly attenuated hyperglycemia and glucose intolerance in genetic (db/db) and dietary fat-induced type 2 diabetic mice as well as in streptozotocin-induced type 1 diabetic mice. MUP1 inhibited the expression of both gluconeogenic genes and lipogenic genes in the liver. Moreover, recombinant MUP1 directly decreased glucose production in primary hepatocyte cultures by inhibiting the expression of gluconeogenic genes. These data suggest that MUP1 regulates systemic glucose and/or lipid metabolism through the paracrine/autocrine regulation of the hepatic gluconeogenic and/or lipogenic programs, respectively.