Identification of Sedum kamtschaticum, Lythrum anceps, and Astilbe chinensis var. davidii as inhibitors of peroxisome-proliferator-activated receptor γ expression and lipid accumulation

2012 ◽  
Vol 55 (5) ◽  
pp. 625-631
Author(s):  
Woo-Seok Jang ◽  
No-Joon Song ◽  
Hyang-Jin Yoon ◽  
Min-Ji Kim ◽  
Jin-Mo Ku ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Abstract 15931: Glycogen Synthase Kinase-3α Plays a Critical Role in the Development of Cardiac Dysfunction During Obesity and Insulin Resistance Through Phosphorylation of Peroxisome Proliferator-Activated Receptor α

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Insulin Resistance ◽  
Cardiac Hypertrophy ◽  
Diastolic Dysfunction ◽  
Cardiac Dysfunction ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Obesity and insulin resistance (IR) lead to impaired cardiac metabolism, resulting in cardiac dysfunction. However, the underlying mechanisms responsible for the development of cardiac dysfunction remain poorly understood. PPARα serves as a key regulator of fatty acid (FA) metabolism in the heart. GSK-3α, a serine/threonine kinase, was dephosphorylated at S21 and activated (2.0 fold, p<0.05) in the hearts of obese mice fed a high-fat diet (HFD) and ob/ob mice. To evaluate the functional significance of GSK-3α upregulation, wild-type (WT) and cardiac specific GSK-3α heterozygous knockout (cGSK-3α HKO) mice were fed a HFD for up to 14 weeks. There was no difference in the food intake or body weight change between WT and cGSK-3α HKO mice. However, cardiac hypertrophy and diastolic dysfunction observed in WT mice were significantly ameliorated in cGSK-3α HKO mice after HFD feeding (8.1± 0.6 and 6.5±0.5, LVW/TL; 24.8±0.9 and 16.6±0.8, deceleration time (DT), all p<0.05). FA oxidation (FAO) (0.81 fold) and ectopic lipid accumulation (Oil Red O staining) were significantly decreased in cGSK-3α HKO mice than in WT mice after HFD feeding. GSK-3α, but not GSK-3β, directly interacted with and phosphorylated PPARα at the ligand binding domain in cardiomyocytes (CMs) and in the heart. PPARα phosphorylation in the heart was significantly increased (2.1 fold, p<0.05) in response to HFD, but it was attenuated in cGSK-3α HKO mice (0.74 fold, p<0.05). Fenofibrate, a PPARα ligand, inhibited GSK-3α-induced PPARα phosphorylation (0.81 fold, p<0.05), reduced ectopic lipid accumulation, FAO (0.84 fold, p<0.05), and attenuated diastolic dysfunction (25.5±3.1 and 18.6±2.5, DT; 0.16±0.04 and 0.08±0.02, EDPVR, all p<0.05) in the heart of HFD fed mice. Collectively, these results suggest that GSK-3α increases PPARα activity through phosphorylation of PPARα, which is inhibited by Fenofibrate. Activation of GSK-3α and consequent phosphorylation of PPARα during obesity and IR could play an important role in the development of cardiac hypertrophy and diastolic dysfunction. Synthetic PPARα ligands inhibit GSK-3α-mediated phosphorylation of PPARα, thereby paradoxically attenuating excessive FA metabolism in cardiomyocytes.

scholarly journals Crocetin Isolated from the Natural Food Colorant Saffron Reduces Intracellular Fat in 3T3-L1 Adipocytes

Foods ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1648
Author(s):  
Elena Jiménez-Ortega ◽  
Aitana Braza-Boïls ◽  
Miguel Burgos ◽  
Natalia Moratalla-López ◽  
Manuel Vicente ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Low Cost ◽  
Natural Food ◽  
Peroxisome Proliferator ◽  
Synthetic Dyes ◽  
Potential Candidate ◽  
Peroxisome Proliferator Activated Receptor ◽  
Food Colorant ◽  
Enhancer Binding Protein ◽  
Diphenyltetrazolium Bromide

Saffron, as a food colorant, has been displaced by low-cost synthetic dyes. These have unhealthy properties; thus, their replacement with natural food colorants is an emerging trend. Obesity is a worldwide health problem due to its associated comorbidities. Crocetin esters (crocins) are responsible for the red saffron color. Crocetin (CCT) exhibits healthful properties. We aimed to broaden the existing knowledge on the health properties of CCT isolated from saffron, to facilitate its consideration as a healthy natural food colorant in the future. We evaluated the ability of CCT (1 and 5 μM) to reduce lipid accumulation during the differentiation of 3T3-L1 preadipocytes. Intracellular fat was quantified by Oil Red O staining. CTT cytotoxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The number and size of lipid droplets were analyzed using WimLipid software. The expression of adipogenic genes (CCAAT/enhancer-binding protein (C/EBPβ, C/EBPδ, C/EBPα), and peroxisome proliferator-activated receptor γ (PPARγ)) was analyzed using quantitative real-time PCR (qRT-PCR). CCT 5 μM decreased intracellular fat by 22.6%, without affecting viability or lipid droplet generation, via a decrease in C/EBPα expression, implicated in lipid accumulation. Thus, CCT is a potential candidate to be included in dietary therapies aimed at reversing adipose tissue accumulation in obesity.

scholarly journals CD36-Mediated Lipid Accumulation and Activation of NLRP3 Inflammasome Lead to Podocyte Injury in Obesity-Related Glomerulopathy

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Jing Zhao ◽  
Hong-liang Rui ◽  
Min Yang ◽  
Li-jun Sun ◽  
Hong-rui Dong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Lipid Accumulation ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Animal Experiments ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Podocyte Injury ◽  
Peroxisome Proliferator Activated Receptor

Podocyte injury critically contributes to the pathogenesis of obesity-related glomerulopathy (ORG). Recently, lipid accumulation and inflammatory responses have been found to be involved in podocyte injury. This study is to explore their role and relationship in podocyte injury of ORG. In animal experiments, the ORG mice developed proteinuria, podocyte injury, and hypertriglyceridemia, accompanied with deregulated lipid metabolism, renal ectopic lipid deposition, activation of NOD-like receptor protein 3 (NLRP3) inflammasome, and secretion of IL-1β of the kidney. The expression of adipose differentiation-related protein (ADRP), CD36, sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor α (PPARα) in renal tissue were increased. In in vitro cell experiments, after cultured podocytes were stimulated with leptin, similar to ORG mice, we found aggravated podocyte injury, formatted lipid droplet, increased expression of ADRP and CD36, activated NLRP3 inflammasome, and released IL-1β. In addition, after blocking CD36 with inhibitor sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA, activation of NLRP3 inflammasome and release of IL-1β are downregulated, and podocyte injury was alleviated. However, after blocking NLRP3 with MCC950, although podocyte injury was alleviated and release of IL-1β was decreased, there was no change in the expression of CD36, ADRP, and intracellular lipid droplets. Taken together, our study suggests that CD36-mediated lipid accumulation and activation of NLRP3 inflammasome may be one of the potential pathogeneses of ORG podocyte injury.

scholarly journals 6-Gingerol Normalizes the Expression of Biomarkers Related to Hypertension via PPARδ in HUVECs, HEK293, and Differentiated 3T3-L1 Cells

PPAR Research ◽  
2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Yong-Jik Lee ◽  
Yoo-Na Jang ◽  
Yoon-Mi Han ◽  
Hyun-Min Kim ◽  
Hong Seog Seo
Keyword(s):  
Side Effects ◽  
Lipid Accumulation ◽  
Umbilical Vein ◽  
New Drugs ◽  
Hek293 Cells ◽  
Immunocytochemical Staining ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor

Hypertension is a disease with a high prevalence and high mortality rates worldwide. In addition, various factors, such as genetic predisposition, lifestyle factors, and the abnormality of organs related to blood pressure, are involved in the development of hypertension. However, at present, there are few available drugs for hypertension that do not induce side effects. Although the therapeutic effects of ginger on hypertension are well established, the precise mechanism has not been elucidated. Therefore, this study was designed to evaluate the antihypertensive mechanism of 6-gingerol, one of the main ingredients of ginger, and to assist in the development of new drugs for hypertension without side effects. The antihypertensive effects and mechanism of 6-gingerol were identified through reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunocytochemical staining for biomarkers involved in hypertension in human umbilical vein endothelial cells (HUVECs), human embryonal kidney cells (HEK293 cells), and mouse preadipocytes (3T3-L1 cells). The lipid accumulation in differentiated 3T3-L1 cells was evaluated by using Oil Red O staining. 6- Gingerol increased the level of phosphorylated endothelial nitric oxide synthase (eNOS) protein but decreased that of vascular cell adhesion protein 1 (VCAM1) and tumor necrosis factor alpha (TNFα) in HUVECs. In HEK293 cells, the expression of the epithelial sodium channel (ENaC) protein was reduced by 6-gingerol. Lipid accumulation was attenuated by 6-gingerol treatment in differentiated 3T3-L1 cells. These effects were regulated via peroxisome proliferator-activated receptor delta (PPARδ). 6-Gingerol ameliorated the expression of biomarkers involved in the development of hypertension through PPARδ in HUVECs, HEK293, and differentiated 3T3-L1 cells.

Evaluation of anti-adipogenic active homoisoflavonoids from Portulaca oleracea

2019 ◽  
Vol 74 (9-10) ◽  
pp. 265-273 ◽  
Author(s):  
Jung Im Lee ◽  
Jung Hwan Oh ◽  
Chang-Suk Kong ◽  
Youngwan Seo
Keyword(s):  
Fatty Acid ◽  
Crude Extract ◽  
Lipid Accumulation ◽  
Target Genes ◽  
Adipogenic Differentiation ◽  
Portulaca Oleracea ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding

Abstract This study was performed to isolate antiobesity components from the crude extract of Portulaca oleracea. The crude extract was partitioned into n-hexane, 85% aqueous methanol, n-butanol, and water fractions. Their effects on adipogenic differentiation were evaluated in 3T3-L1 cells. Among the solvent fractions from P. olearacea, the 85% aq. MeOH effectively reduced the levels of lipid accumulation. Further purification of 85% aq. MeOH led to the isolation of the known homoisoflavonoids 1–4, as the active substances. The administration of homoisoflavonoids to adipocyte cells decreased the lipid accumulation and glucose consumption and increased the release of glycerol into culture medium. In particular, homoisoflavonoid 3 effectively down-regulated the adipogenic transcription genes such as peroxisome proliferator activated receptor-γ (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPα), and adipogenic target genes such as fatty acid binding protein 4 (FABP4), fatty acid transport protein 1 (FATP1), and acyl-CoA synthase 1 (ACS1).

Abstract 13671: GSK-3α Directly Regulates Lipid Metabolism Through Obesity-linked Phosphorylation of PPARα

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Tong Liu ◽  
Hong Li ◽  
Junichi Sadoshima
Keyword(s):  
Lipid Metabolism ◽  
Cardiac Dysfunction ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Body Weight Gain ◽  
Glycogen Synthesis ◽  
Mass Spectrometry Analysis ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Peroxisome Proliferator Activated Receptor

Obesity impairs lipid metabolism and leads to cardiac dysfunction, where peroxisome proliferator-activated receptor α (PPARα) serves as a key regulator of lipid metabolism. Glycogen synthase kinase-3α (GSK-3α), a serine-threonine kinase, is markedly upregulated in the heart of obese mice, suppressing glycogen synthesis. However, the functional significance of upregulated GSK-3α in lipid metabolism remains unknown. Here we show that GSK-3α directly upregulates lipid metabolism and aggravates cardiac lipotoxicity in obesity. GSK-3α activity was enhanced by palmitic acid (PA) in the nucleus in cardiomyocytes (CMs), and knockdown of GSK-3α suppressed PA-induced activation of PPARα. GSK-3α, but not GSK-3β, directly interacted with PPARα. Mass spectrometry analysis revealed that GSK-3α phosphorylates PPARα at Ser280, located in the ligand binding domain. A PPARα phospho-mimicking mutant (PPARα-S280D) exhibited an increase in both the interaction of PPARα with RXR and its DNA binding, enhancing PPARα activity and stimulating expression of lipid metabolism-related genes, including Cpt1b, CD36 and PDHK4, in CMs. High-fat diet (HFD)-fed mice displayed increased GSK-3α activity and PPARα phosphorylation in the heart. Cardiac-specific haploinsufficiency of GSK-3α normalized HFD-induced lipid accumulation (Oil Red O staining), abnormally enhanced palmitate oxidation (0.82 fold, p<0.05), cardiac hypertrophy and diastolic dysfunction (0.36 fold in EDPVR, p<0.05) without affecting body weight gain or food intake. While adenovirus-mediated overexpression of PPARα in the heart exacerbated HFD-induced lipid dysregulation and cardiac dysfunction, that of PPARα phospho-resistant mutant (PPARα-S280A) failed to facilitate lipid metabolism and cardiac dysfunction in the presence of a HFD. Notably, a PPARα ligand, fenofibrate, allosterically inhibited PPARα phosphorylation in obese mice by interfering with the interaction between GSK-3α and PPARα, and improved HFD-induced lipid accumulation and cardiac dysfunction. These data show that GSK-3α directly regulates lipid metabolism through Ser280 phosphorylation of PPARα, and that its phosphorylation could be a novel therapeutic target for obesity-related cardiac dysfunction.

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