Regulation of the metabolism of apolipoprotein M and sphingosine 1-phosphate by hepatic PPARγ activity

2018 ◽  
Vol 475 (12) ◽  
pp. 2009-2024 ◽  
Author(s):  
Makoto Kurano ◽  
Hitoshi Ikeda ◽  
Naoyuki Iso-O ◽  
Masumi Hara ◽  
Kazuhisa Tsukamoto ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Mouse Liver ◽  
Kinase Activity ◽  
Sphingosine Kinase ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apolipoprotein M ◽  
Adenoviral Gene Transfer ◽  
Sphingosine 1 Phosphate

Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multifunctional bioactive lipid. Since peroxisome proliferator-activated receptor γ (PPARγ) is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARγ. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARγ in HepG2 cells and found that both the overexpression and the knockdown of PPARγ decreased apoM expression and S1P synthesis. When we activated or suppressed the PPARγ more mildly with pioglitazone or GW9662, we found that pioglitazone suppressed apoM expression and S1P synthesis, while GW9662 increased them. Next, we overexpressed PPARγ in mouse liver through adenoviral gene transfer and observed that both the plasma and hepatic apoM levels and the plasma S1P levels decreased, while the hepatic S1P levels increased, in the presence of enhanced sphingosine kinase activity. Treatment with pioglitazone decreased both the plasma and hepatic apoM and S1P levels only in diet-induced obese mice. Moreover, the overexpression of apoM increased, while the knockdown of apoM suppressed PPARγ activities in HepG2 cells. These results suggested that PPARγ regulates the S1P levels by modulating apoM in a bell-shaped manner, with the greatest levels of apoM/S1P observed when PPARγ was mildly expressed and that hepatic apoM/PPARγ axis might maintain the homeostasis of S1P metabolism.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

scholarly journals Hyperthyroidism Evokes Myocardial Ceramide Accumulation

2015 ◽  
Vol 35 (2) ◽  
pp. 755-766 ◽  
Author(s):  
Agnieszka Mikłosz ◽  
Bartłomiej Łukaszuk ◽  
Adrian Chabowski ◽  
Filip Rogowski ◽  
Krzysztof Kurek ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Cardiac Physiology ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sphingosine 1 Phosphate ◽  
Male Wistar Rats ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Cpt I ◽  
Amp Activated Protein Kinase ◽  
Ceramide Accumulation

Background: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T3) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T3 treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), β-hydroxyacyl-CoA dehydrogenase (β-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). Conclusions: We conclude that prolonged T3 treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

Abstract 74: Heme Oxygenase-PPARα Induction of FGF21 in Hepatocytes Recruits pAMPK/pAKT and Attenuates Insulin Resistance in Obese Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Terry D Hinds ◽  
Nader G Abraham
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Heme Oxygenase ◽  
Serum Adiponectin ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Hep G2 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Homeostasis

The peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that is known to regulate glucose and lipid homeostasis and increases expression of the hormone fibroblast growth factor 21 (FGF21), which is secreted to blood, increases phosphorylation of AMPK and AKT in adipocytes and has been purported to stimulate adiponectin synthesis. The heme oxygenase (HO) system is functionally important for reducing ROS and inflammation whose induction has been shown to increase serum adiponectin levels and affect lowering of blood glucose and fatty acids. This study was designed to examine the hypothesis that a HO-1-PPARα crosstalk could elevate hepatic FGF21 thus leading to enhanced adiponectin secretion and abatement of metabolic imbalance. Preliminary experiments were conducted in human hepatocellular carcinoma cells (Hep G2) cultured in the absence or presence of the HO-1 inducer, cobalt protoporphyrin (CoPP, 2μmoles/l). A 2.0 fold induction of HO-1 in Hep G2 cells by CoPP (p<0.05) increased expression of FGF21 1.5 fold (n=3, p=0.0119 vs. vehicle control) without affecting PPARα expression. Additional experiments in obese (ob/ob) mice treated with CoPP (5mg/kg/day) resulted in 2 fold (p<0.05) increase of FGF21 mRNA expression in liver as compared to mice treated with the vehicle. These observations were complemented by blood glucose measurements, which showed significant attenuation in obese mice treated with CoPP (vehicle: 285.0±24 vs. CoPP: 160.0±27.3, p<0.05, n= 5), along with enhancement of adiponectin levels in CoPP treated obese mice (p<0.05). Taken together these results demonstrate that HO-1 could increase serum adiponectin levels and insulin sensitivity by elevating hepatic FGF21 levels. Our overall hypothesis is that the HO-1 can stimulate PPARα activity with resultant activation of hepatic FGF21 secretion and that this HO-PPARα-FGF21 axis could work in concert to modulate the development of insulin resistance and diabetes.

scholarly journals Curcumin improves glycolipid metabolism through regulating peroxisome proliferator activated receptor γ signalling pathway in high-fat diet-induced obese mice and 3T3-L1 adipocytes

2017 ◽  
Vol 4 (11) ◽  
pp. 170917 ◽  
Author(s):  
Yanyun Pan ◽  
Dandan Zhao ◽  
Na Yu ◽  
Tian An ◽  
Jianan Miao ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Signalling Pathway ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glycolipid Metabolism

Curcumin is an active component derived from Curcuma longa L. which is a traditional Chinese medicine that is widely used for treating metabolic diseases through regulating different molecular pathways. Here, in this study, we aimed to comprehensively investigate the effects of curcumin on glycolipid metabolism in vivo and in vitro and then determine the underlying mechanism. Male C57BL/6 J obese mice and 3T3-L1 adipocytes were used for in vivo and in vitro study, respectively. Our results demonstrated that treatment with curcumin for eight weeks decreased body weight, fat mass and serum lipid profiles. Meanwhile, it lowered fasting blood glucose and increased the insulin sensitivity in high-fat diet-induced obese mice. In addition, curcumin stimulated lipolysis and improved glycolipid metabolism through upregulating the expressions of adipose triglyceride lipase and hormone-sensitive lipase, peroxisome proliferator activated receptor γ/α (PPARγ/α) and CCAAT/enhancer binding proteinα (C/EBPα) in adipose tissue of the mice. In differentiated 3T3-L1 cells, curcumin reduced glycerol release and increased glucose uptake via upregulating PPARγ and C/EBPα. We concluded that curcumin has the potential to improve glycolipid metabolism disorders caused by obesity through regulating PPARγ signalling pathway.

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