Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

Montagner, Alexandra; Polizzi, Arnaud; Fouché, Edwin; Ducheix, Simon; Lippi, Yannick; Lasserre, Frédèric; Barquissau, Valentin; Régnier, Marion; Lukowicz, Céline; Benhamed, Fadila; Iroz, Alison; Bertrand‐Michel, Justine; Saati, Talal Al; Cano, Patricia; Mselli-Lakhal, Laïla; Mithieux, Gilles; Rajas, Fabienne; Lagarrigue, Sandrine; Pineau, Thierry; Loiseau, Nicolas; Postic, Catherine; Langin, Dominique; Wahli, Walter; Guillou, Hervé

doi:10.1136/gutjnl-2015-310798

Cited by 531 publications

(541 citation statements)

References 53 publications

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“…Lipid storage and the burning of fat are mediated by fat sensing nuclear receptors, PPAR␥ and PPAR␣, where PPAR␥ stores fat and PPAR␣ burns lipids by ␤-oxidation. Hepatic PPAR␣ increases the fat burning and glucose-lowering hormone, fibroblast growth factor 21 (FGF21), which causes a dramatic decrease in lipid accumulation in whole animals and sensitization to peripheral insulin signaling (12)(13)(14)(15)(16)(17)(18)(19). A reduction in PPAR␣ in the liver causes the development of fatty liver and inflammation (12,19).…”

mentioning

confidence: 99%

“…Hepatic PPAR␣ increases the fat burning and glucose-lowering hormone, fibroblast growth factor 21 (FGF21), which causes a dramatic decrease in lipid accumulation in whole animals and sensitization to peripheral insulin signaling (12)(13)(14)(15)(16)(17)(18)(19). A reduction in PPAR␣ in the liver causes the development of fatty liver and inflammation (12,19). The GR␤ isoform has been shown to increase immune cell proliferation by inhibiting the anti-inflammatory actions of GCs (3,20), as well as increase inflammatory pathways in liver (11).…”

mentioning

confidence: 99%

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Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Marino

Stechschulte

Stec

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldGlucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GR␣, as the GR␤ isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GR␤ inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GR␤ expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GR␤ overexpression (GR␤-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GR␤-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-B signaling and increased tumor necrosis factor ␣ (TNF␣) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GR␤-Ad mice had increased glycogen synthase kinase 3␤ (GSK3␤) activity and reduced hepatic PPAR␣ and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the ␤-oxidation pathway. In conclusion, GR␤ antagonizes the GC-induced signaling during fasting via GR␣ and the PPAR␣-FGF21 axis that reduces fat burning. Furthermore, hepatic GR␤ increases inflammation, which leads to hepatic lipid accumulation.

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confidence: 99%

mentioning

confidence: 99%

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Marino

Stechschulte

Stec

et al. 2016

Journal of Biological Chemistry

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“…In the case of PPAR , defective fatty acid metabolism can result in the development of nonalcoholic fatty liver disease [33].…”

Section: Resultsmentioning

confidence: 99%

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Ellul¹,

Shoemake²

2017

Nuclear Receptor Research

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Abstract. This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome-hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR) partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPAR fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPAR and/or _LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the "tried and tested" Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.

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“…PPARα is coactivated by PGC-1α to enhance the fatty acid oxidation pathway (37,38). Thus, PGC-1α may be also the effector of triglyceride metabolism during SAK-HV treatment.…”

Section: Stat3-c/ebpβ-pgc-1α Was Screened Out By Weighted Gene Co-expmentioning

confidence: 99%

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

Zhang¹,

Huang²,

Jing³

et al. 2017

Theranostics

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The accumulations of excess lipids within liver and serum are defined as non-alcoholic fatty liver disease (NAFLD) and hyperlipemia respectively. Both of them are components of metabolic syndrome that greatly threaten human health. Here, a recombinant fusion protein (SAK-HV) effectively treated NAFLD and hyperlipemia in high-fat-fed ApoE -/- mice, quails and rats within just 14 days. Its triglyceride and cholesterol-lowering effects were significantly better than that of atorvastatin during the observation period. We explored the lipid-lowering mechanism of SAK-HV by the hepatic transcriptome analysis and serials of experiments both in vivo and in vitro . Unexpectedly, SAK-HV triggered a moderate energy and material-consuming liver proliferation to dramatically decrease the lipids from both serum and liver. We provided the first evidence that PGC-1α mediated the hepatic synthesis of female hormones during liver proliferation, and proposed the complement system-induced PGC-1α-estrogen axis via the novel STAT3-C/EBPβ-PGC-1α pathway in liver as a new energy model for liver proliferation. In this model, PGC-1α ignited and fueled hepatocyte activation as an “igniter”; PGC-1α-induced estrogen augmented the energy supply of PGC-1α as an “ignition amplifier”, then triggered the hepatocyte state transition from activation to proliferation as a “starter”, causing triglyceride and cholesterol-lowering effects via PPARα-mediated fatty acid oxidation and LDLr-mediated cholesterol uptake, respectively. Collectively, the SAK-HV-triggered distinctive lipid-lowering strategy based on the new energy model of liver proliferation has potential as a novel short-period biotherapy against NAFLD and hyperlipemia.

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Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD

Cited by 531 publications

References 53 publications

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

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