Effects of peroxisome proliferator-activated receptor α activation on pathways contributing to cholesterol homeostasis in rat hepatocytes

Jossic-Corcos, Catherine Le; Duclos, Sandrine; Ramirez, Leyla C.; Zaghini, Isabelle; Chevillard, Grégory; Martin, Pascal G.P.; Pineau, Thierry; Bournot, Paulette

doi:10.1016/j.bbalip.2004.04.004

Cited by 27 publications

(10 citation statements)

References 46 publications

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“…The up-regulation of SREBP-1 expression was observed in fenofibrate-treated Pparα +/+ mice, and this effect was strongly impaired in Pparα −/− mice. The results indicate that the induction of SREBP-1 expression observed in fenofibrate-treated mice is dependent on PPARα activation, similar to the changes observed in other studies [25], [26], [35], [36]. Fibrates also stimulate the β-oxidation of fatty acids, leading to fatty acid depletion, which increases SREBP-1c expression [15].…”

Section: Discussionsupporting

confidence: 87%

Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

Fang

Wang

et al. 2014

PLoS ONE

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Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an adverse effect of fibrates on the pathogenesis of hepatic steatosis.

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Section: Discussionsupporting

confidence: 87%

Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

Fang

Wang

et al. 2014

PLoS ONE

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“…It is not unusual for therapeutic targets to be present in non-target tissues however it has not always been investigated. In the case of thiazolidinediones there was conflicting evidence as to the level and importance of the expression of PPAR-α [49] and PPAR-γ [50] in vascular smooth muscle cells and hence the contribution that such targets may make to the vascular actions of these drugs [51]. Our data allows for a favourable understanding that GKAs do not intensify the deleterious actions of glucose on vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 87%

Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Al-aryahi

Kamato

Getachew

et al. 2014

Cardiovasc Diabetol

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BackgroundPharmaceutical interventions for diabetes aim to control glycaemia and to prevent the development of complications, such as cardiovascular diseases. Some anti-hyperglycaemic drugs have been found to have adverse cardiovascular effects in their own right, limiting their therapeutic role. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. Glucokinase activators (GKAs) are novel agents for diabetes which act by enhancing the formation of glucose-6-phosphate leading to increased insulin production and subsequent suppression of blood glucose. Little, however, is known about the direct effects of GKAs on cardiovascular cells.MethodsThe effect of the GKAs RO28-1675 and Compound A on glucose utilisation in bovine aortic endothelial cells (BAEC) and rat MIN6 was observed by culturing the cells at high and low glucose concentration in the presence and absence of the GKAs and measuring glucose consumption. The effect of RO28-1675 at various concentrations on glucose-dependent signalling in BAEC was observed by measuring Smad2 phosphorylation by Western blotting. The effect of RO28-1675 on TGF-β stimulated proteoglycan synthesis was measured by 35S-SO4 incorporation and assessment of proteoglycan size by SDS-PAGE. The effects of RO28-1675 on TGF-β mediated Smad2C phosphorylation in BAEC was observed by measurement of pSmad2C levels. The direct actions of RO28-1675 on vascular reactivity were observed by measuring arteriole tone and lumen diameter.ResultsGKAs were demonstrated to increase glucose utilisation in pancreatic but not endothelial cells. Glucose-activated Smad2 phosphorylation was decreased in a dose-dependent fashion in the presence of RO28-1675. No effect of RO28-1675 was observed on TGF-β stimulated proteoglycan production. RO28-1675 caused a modest dilation in arteriole but not contractile sensitivity.ConclusionsGKA RO28-1675 did not increase glucose consumption in endothelial cells indicating the absence of glucokinase in those cells. No direct deleterious actions, in terms of atherogenic changes or excessive vasoactive effects were seen on cells or vessels of the cardiovascular system in response to GKAs. If reflected in vivo, these drugs are unlikely to have their use compromised by direct cardiovascular toxicity.

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“…Furthermore, the SREBP1c mRNA levels were lower in the livers of PPAR␣-null mice than in the WT mice (30). Accordingly, the level of SREBP1c significantly increased in fenofibrate-treated WT mice (31), but not in PPAR␣-null mice (32). Thus, it is feasible to hypothesize that PPAR␣ gene expression regulation in general, and the SREBP1c expression in particular, may depend on an acting ligand nature.…”

Section: Discussionmentioning

confidence: 99%

“…The oligonucleotides corresponding to the DR1 binding site (5Ј-CCCTTCGTTAAAGGGTCAAA-GCAGAGAAGTCCTGGCCC-3Ј), the LXRE1 binding site (5Ј-GGAGCTGAGGGCCAGTGACCGCCAGTAACCCCG-GCAGACGCTGG-3Ј), and the LXRE2 binding site (5Ј-CGG-GTTAAAGGCGGACGTCCGCTAGTAACCCCAACCCCA-TTCAGC-3Ј) were annealed with the complementary sequence by incubation at 85°C for 10 min in 70 mM Tris-HCl (pH 7.5), 13 mM MgCl, 1.3 mM EDTA, 1.3 mM spermidine, and 6.7 mM DTT with overnight cooling. A 300-ng aliquot of the probe was labeled with 20 units of T4 polynucleotide kinase in the presence of 40 Ci [␥- 32 P]dATP at a final volume of 10 l for 30 min at 37°C and purified in Sephadex G25 columns. Binding reactions were carried out for 20 min at room temperature using in vitro-translated human PPAR␣, LXR␣ and RXR␣ prepared with the TNT T7-coupled reticulocyte lysate system (Promega), 9 fmol of probe, and 2 g poly (dI/dC) in the binding buffer (20 mM HEPES (pH 8.0), 0.1 mM EDTA, 50s mM ClNA, 1 mM DTT, 5% glycerol, and 5 mM Cl 2 Mg).…”

Section: Methodsmentioning

confidence: 99%

Human SREBP1c Expression in Liver Is Directly Regulated by Peroxisome Proliferator-activated Receptor α (PPARα)

Fernández-Alvarez

Alvarez

González

et al. 2011

Journal of Biological Chemistry

110

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Sterol regulatory element binding proteins (SREBPs) regulate the expression of a number of enzymes, which catalyze the synthesis of fatty acids, cholesterol, triglycerides, and phospholipids. SREBP1c is the most relevant isoform in the adult liver, and its expression is controlled by the nutritional state. Transcriptional regulation studies into the SREBP1c gene, performed in the last few years, have improved our knowledge of the variability of signals that converge on its promoter region. Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. The present study aimed to perform a detailed analysis of the human SREBP1c gene promoter structure in liver cells by focusing on responses to diverse metabolic signals. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP1c transcription regulation mediated by insulin and cholesterol derivatives. We discovered that peroxisome proliferation-activated receptor alpha (PPAR␣) agonists enhance the activity of the SREBP1c promoter; a DR1 element, at ؊453 in the human promoter was involved in this activation. Moreover, PPAR␣ agonists act in cooperation with LXR or insulin to induce lipogenesis. Collectively, our results identify PPAR␣ as a novel regulatory factor in SREBP1c regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation.The prevalence of overweight and obesity is increasing worldwide at an alarming rate. An excess amount of body fat not only leads to reduced quality of life and immense healthcare-associated costs but also increases risk of death. Indeed, obesity has been related to a number of cardiovascular and metabolic disorders such as hypertension, type 2 diabetes, hyperinsulinemia, dyslipidemia, and atherosclerosis, all of them defining features of the metabolic syndrome. Beyond obesity and a number of independent factors, the other etiological factor of metabolic syndrome is insulin resistance, commonly considered to be of greater priority in pathogenesis (1, 2).The discovery of sterol regulatory element binding proteins (SREBPs) 4 was critical for our understanding of hepatic cholesterol homeostasis. SREBP1c, one of three SREBPs members of the basic helix-loop-helix family of transcription factors, is essential for the genomic actions of insulin on both carbohydrate and lipid metabolism (3) and plays a central role in the molecular biochemistry of metabolic syndrome. The SREBP1c expression is controlled by nutritional status. Fasting lowers SREBP1c mRNA and protein levels, whereas they are strongly induced in a fed state, followed by a compatible pattern of nutritional changes in lipogenic genes (4). Accordingly, changes in the activity of this transcription factor may be the key to linking insulin resistance with other obesity-associated metabolic disorders.Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily. The LXR subfamily co...

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Effects of peroxisome proliferator-activated receptor α activation on pathways contributing to cholesterol homeostasis in rat hepatocytes

Cited by 27 publications

References 46 publications

Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Human SREBP1c Expression in Liver Is Directly Regulated by Peroxisome Proliferator-activated Receptor α (PPARα)

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