Platyphylloside Isolated From Inhibit Adipocyte Differentiation and Induce Lipolysis Via Regulating Adipokines Including PPARγ in 3T3-L1 Cells.
Lee Mina,Sung Sang Hyun
Pharmacognosy magazine
BACKGROUND:Obesity causes or aggravates many health problems, both independently and in association with several pathological disorders, including Type II diabetes, hypertension, atherosclerosis, and cancer. Therefore, we screened small compounds isolated from natural products for the development of anti-obesity drugs. OBJECTIVE:The purpose of this study was to investigate the anti-adipogenic activities of platyphylloside, diarylheptanoid isolated from , which was selected based on the screening using 3T3-L1 cells. MATERIALS AND METHODS:To evaluate the inhibition of adipocyte differentiation and lipolysis, lipid contents of BPP on were measured using Oil Red O staining in 3T3-L1 cells. The mRNA and protein expression levels of various adipokines were measured by Quantitative real-time PCR and Western blotting analysis, respectively. RESULTS:Platyphylloside showed significant inhibitory activity on adipocyte differentiation in 3T3-L1 cells and suppressed adipocyte differentiation even in the presence of troglitazone, a PPARγ agonist. Platyphylloside might suppress adipocyte differentiation through PPARγ, C/EBPα, and SREBP1-induced adipogenesis, which is synergistically associated with downstream adipocyte-specific gene promoters such as aP2, FAS, SCD-1, LPL, and Adiponectin. In addition, platyphylloside affected lipolysis by down-regulating perilipin and HSL and up-regulating TNFα. CONCLUSION:Taken together, the results reveal that platyphylloside has anti-adipogenic activity and highlight its potential in the prevention and treatment of obesity. SUMMARY:The extract of B. bark and its isolate, BPP, had anti-adipogenic activity in 3T3-L1 cells via suppression of adipocyte differentiation from preadipocytes.Treatment with BPP significantly down-regulated the expression of PPARγ, C/EBP, C/EBPβ, C/EBPδ, SREBP1c, SCD-1, FAS, aP2 and LPL.BPP induced a lipolytic response in mature adipocytes via up-regulation krof TNFá and down-regulation of HSL, perilipin, PPARγ, PDE3B, and Gia1.BPP is a novel potential agent in the prevention and treatment of obesity through its anti-adipogenic activities and lipolysis. DMEM: Dulbecco's modified Eagle's medium, FBS: fetal bovine serum, ORO: Oil Red O, PBS: phosphate buffered saline, RT: room temperature, PPAR: peroxisome proliferator-activated receptor, C/EBP: CCAAT/enhancer-binding protein, SREBP1: sterol regulatory element binding protein 1, SCD-1: steroyl-coenzyme A desaturase 1, LPL: lipoprotein lipase, aP2: adipocyte fatty acid binding protein, FAS: fatty acid synthase, HSL: hormone sensitive lipase, Giα: GPT binding protein, PDE3B: phosphodiesterase 3B, TNFα: tumor necrosis factor α, GAPDH: glyceraldehyde 3-phosphate dehydrogenase, SD: standard deviation, EGCG: epigallocatechin-3-gallate, TZD: thiazolidinediones.
10.4103/0973-1296.192208
New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk?
Olkkonen Vesa M,Sinisalo Juha,Jauhiainen Matti
Atherosclerosis
Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are at present the central molecular targets for therapies designed to reduce TRL, and there are new drugs emerging that suppress their expression or inhibit the function of these two key proteins. The medications targeting these components are biological, either human monoclonal antibodies or antisense oligonucleotides. In this article, we briefly review the mechanisms of action of ANGPTL3 and apoC-III, the reasons why they have been considered promising targets of novel therapies for CVD, as well as the current status and the most important results of their clinical trials.
10.1016/j.atherosclerosis.2018.03.019
Lipolytic PPAR activation: new insights into the intersection of triglycerides and inflammation?
Ziouzenkova Ouliana,Plutzky Jorge
Current opinion in clinical nutrition and metabolic care
PURPOSE OF REVIEW:To examine connections between triglyceride metabolism and inflammation, especially as they relate to transcriptional regulation through peroxisomal proliferator activated receptors activation. RECENT FINDINGS:Peroxisomal proliferator activated receptors, members of the steroid hormone nuclear receptor family, have been of particular interest as a mechanism through which different dietary components might control gene expression. Extensive prior work has defined the central role peroxisomal proliferator activated receptors play in many key metabolic responses, including glucose control and lipid metabolism. Emerging evidence suggests peroxisomal proliferator activated receptor activation may limit inflammation and atherosclerosis. The demonstration that certain fatty acids can activate peroxisomal proliferator activated receptors belies the potential link between nutritional components and peroxisomal proliferator activated receptor responses. Interest in this connection had been heightened by recent evidence that lipolysis in certain situations can both generate peroxisomal proliferator activated receptor ligands and limit some known inflammatory responses. SUMMARY:Lipolytic peroxisomal proliferator activated receptor activation suggests new ways in which to reconsider triglycerides and the distal consequences of their metabolism, including the possible effects on inflammation and atherosclerosis.
10.1097/01.mco.0000134358.46159.61
Dicer in Macrophages Prevents Atherosclerosis by Promoting Mitochondrial Oxidative Metabolism.
Wei Yuanyuan,Corbalán-Campos Judit,Gurung Rashmi,Natarelli Lucia,Zhu Mengyu,Exner Nicole,Erhard Florian,Greulich Franziska,Geißler Claudia,Uhlenhaut N Henriette,Zimmer Ralf,Schober Andreas
Circulation
BACKGROUND:Alternative macrophage activation, which relies on mitochondrial oxidative metabolism, plays a central role in the resolution of inflammation and prevents atherosclerosis. Moreover, macrophages handle large amounts of cholesterol and triglycerides derived from the engulfed modified lipoproteins during atherosclerosis. Although several microRNAs regulate macrophage polarization, the role of the microRNA-generating enzyme Dicer in macrophage activation during atherosclerosis is unknown. METHODS:To evaluate the role of Dicer in atherosclerosis, Apoe mice with or without macrophage-specific Dicer deletion were fed a high-fat diet for 12 weeks. Anti-argonaute 2 RNA immunoprecipitation chip and RNA deep sequencing combined with microRNA functional screening were performed in the Dicer wild-type and knockout bone marrow-derived macrophages to identify the individual microRNAs and the mRNA targets mediating the phenotypic effects of Dicer. The role of the identified individual microRNA and its target in atherosclerosis was determined by tail vein injection of the target site blockers in atherosclerotic Apoe mice. RESULTS:We show that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited whereas lipid-filled foam cell formation was exacerbated in Dicer-deficient macrophages as a result of impaired mitochondrial fatty acid oxidative metabolism. Rescue of microRNA (miR)-10a, let-7b, and miR-195a expression restored the oxidative metabolism in alternatively activated Dicer-deficient macrophages. Suppression of ligand-dependent nuclear receptor corepressor by miR-10a promoted fatty acid oxidation, which mediated the lipolytic and anti-inflammatory effect of Dicer. miR-10a expression was negatively correlated to the progression of atherosclerosis in humans. Blocking the interaction between ligand-dependent nuclear receptor corepressor and miR-10a by target site blockers aggravated atherosclerosis development in mice. CONCLUSIONS:Dicer plays an atheroprotective role by coordinately regulating the inflammatory response and lipid metabolism in macrophages through enhancing fatty acid-fueled mitochondrial respiration, suggesting that promoting Dicer/miR-10a-dependent metabolic reprogramming in macrophages has potential therapeutic implications to prevent atherosclerosis.
10.1161/CIRCULATIONAHA.117.031589
The Gene and Protein Expression of the Main Components of the Lipolytic System in Human Myocardium and Heart Perivascular Adipose Tissue. Effect of Coronary Atherosclerosis.
Knapp Małgorzata,Górski Jan,Lewkowicz Janina,Lisowska Anna,Gil Monika,Wójcik Beata,Hirnle Tomasz,Chabowski Adrian,Mikłosz Agnieszka
International journal of molecular sciences
The aim of our study was to examine the regulation of triacylglycerols (TG) metabolism in myocardium and heart perivascular adipose tissue in coronary atherosclerosis. Adipose triglyceride lipase (ATGL) is the major TG-hydrolase. The enzyme is activated by a protein called comparative gene identification 58 (CGI-58) and inhibited by a protein called G0/G1 switch protein 2 (G0S2). Samples of the right atrial appendage and perivascular adipose tissue were obtained from two groups of patients: 1-with multivessel coronary artery disease qualified for coronary artery bypass grafting (CAD), 2-patients with no atherosclerosis qualified for a valve replacement (NCAD). The mRNA and protein analysis of ATGL, HSL, CGI-58, G0S2, FABP4, FAT/CD36, LPL, β-HAD, CS, COX4/1, FAS, SREBP-1c, GPAT1, COX-2, 15-LO, and NFκβ were determined by using real-time PCR and Western Blot. The level of lipids (i.e., TG, diacylglycerol (DG), and FFA) was examined by GLC. We demonstrated that in myocardium coronary atherosclerosis increases only the transcript level of G0S2 and FABP4. Most importantly, ATGL, β-HAD, and COX4/1 protein expression was reduced and it was accompanied by over double the elevation in TG content in the CAD group. The fatty acid synthesis and their cellular uptake were stable in the myocardium of patients with CAD. Additionally, the expression of proteins contributing to inflammation was increased in the myocardium of patients with coronary stenosis. Finally, in the perivascular adipose tissue, the mRNA of G0S2 was elevated, whereas the protein content of FABP-4 was increased and for COX4/1 diminished. These data suggest that a reduction in ATGL protein expression leads to myocardial steatosis in patients with CAD.
10.3390/ijms21030737
CB1 Receptor-Dependent and Independent Induction of Lipolysis in Primary Rat Adipocytes by the Inverse Agonist Rimonabant (SR141716A).
Müller Günter A,Herling Andreas W,Wied Susanne,Müller Timo D
Molecules (Basel, Switzerland)
(1) Background: Acute administration of the cannabinoid receptor 1 (CB1R) inverse agonist Rimonabant (SR141716A) to fed Wistar rats was shown to elicit a rapid and short-lasting elevation of serum free fatty acids. (2) Methods: The effect of Rimonabant on lipolysis in isolated primary rat adipocytes was studied to raise the possibility for direct mechanisms not involving the (hypothalamic) CB1R. (3) Results: Incubation of these cells with Rimonabant-stimulated lipolysis to up to 25% of the maximal isoproterenol effect, which was based on both CB1R-dependent and independent mechanisms. The CB1R-dependent one was already effective at Rimonabant concentrations of less than 1 µM and after short-term incubation, partially additive to β-adrenergic agonists and blocked by insulin and, in part, by adenosine deaminase, but not by propranolol. It was accompanied by protein kinase A (PKA)-mediated association of hormone-sensitive lipase (HSL) with lipid droplets (LD) and dissociation of perilipin-1 from LD. The CB1R-independent stimulation of lipolysis was observed only at Rimonabant concentrations above 1 µM and after long-term incubation and was not affected by insulin. It was recapitulated by a cell-free system reconstituted with rat adipocyte LD and HSL. Rimonabant-induced cell-free lipolysis was not affected by PKA-mediated phosphorylation of LD and HSL, but abrogated by phospholipase digestion or emulsification of the LD. Furthermore, LD isolated from adipocytes and then treated with Rimonabant (>1 µM) were more efficient substrates for exogenously added HSL compared to control LD. The CB1R-independent lipolysis was also demonstrated in primary adipocytes from fed rats which had been treated with a single dose of Rimonabant (30 mg/kg). (4) Conclusions: These data argue for interaction of Rimonabant (at high concentrations) with both the LD surface and the CB1R of primary rat adipocytes, each leading to increased access of HSL to LD in phosphorylation-independent and dependent fashion, respectively. Both mechanisms may lead to direct and acute stimulation of lipolysis at peripheral tissues upon Rimonabant administration and represent targets for future obesity therapy which do not encompass the hypothalamic CB1R.
10.3390/molecules25040896
Sulfhydration of perilipin 1 is involved in the inhibitory effects of cystathionine gamma lyase/hydrogen sulfide on adipocyte lipolysis.
Ding Yajun,Wang Huamin,Geng Bin,Xu Guoheng
Biochemical and biophysical research communications
Hydrogen sulfide (HS) is a novel adipokine mediating glucose uptake, lipid storage and mobilization, thus contributing to the genesis of obesity and associated diseases. Our previous work demonstrated that HS inhibited isoproterenol-stimulated lipolysis by reducing the phosphorylation of perilipin 1 (plin-1), a lipid-droplet protein blocking lipase access. How HS modulates plin-1 phosphorylation is still unclear. Our present study found that an HS donor slightly increased adipose tissue weight and reduced lipolysis in mice; by contrast, deleting the key HS generation enzyme cystathionine gamma lyase (CSE) in adipocytes lowered adipose accumulation and enhanced lipolysis. Intriguingly, an HS donor induced sulfhydration of plin-1 but not hormone-sensitive lipase, and CSE deletion abolished the post-translational modification of plin-1. During isoproterenol-stimulated lipolysis, plin-1 sulfhydration was associated with reduced phosphorylation, and removing sulfhydration by dithiothreitol recovered the phosphorylation. Finally, plin-1 knockout abolished the effect of HS on lipolysis, which indicates that plin-1 sulfhydration is a major direct target of HS in lipolysis. We have identified a new post-translation modification, sulfhydration (direct action by HS) of plin-1, causing reduced phosphorylation then decreased lipolysis. This finding also highlights a novel molecular regulatory mechanism of lipolysis.
10.1016/j.bbrc.2019.10.192