Microarray Analysis of Gene Expression Changes in Mouse Liver Induced by Peroxisome Proliferator- Activated Receptor α Agonists

doi:10.1006/bbrc.2001.6319

Biochemical and Biophysical Research Communications

Volume 290, Issue 3, 25 January 2002, Pages 1114-1122

https://doi.org/10.1006/bbrc.2001.6319 Get rights and content

Abstract

We used a microarray technique to investigate changes of gene expression in liver induced by two peroxisome proliferator-activated receptor α (PPARα) agonists, a strong PPARα agonist, Wy-14,643, and a marketed fibrate drug, fenofibrate. The purposes of this work are: 1) to examine whether or not gene expression is altered in different ways by these two PPARα agonists and 2) to find genes whose expression has not been previously reported to be affected by PPARα agonists. Mice were treated orally with 100 mg/kg fenofibrate, or 30 mg/kg or 100 mg/kg Wy-14,643, and the liver was collected on Day 2 or 3. mRNA was extraction from liver, and subjected to microarray analysis. Previously reported induction or reduction of gene expression, e.g. genes involved in β-oxidation and lipid metabolism, was confirmed in our study. Scatter plot analysis indicated that the changes of gene expression pattern induced by fenofibrate and Wy-14,643 were almost identical. However, expression levels of metallothionein 1 and 2 mRNAs were different: no change of hepatic metallothionein 1 and 2 mRNA expression was induced by 100 mg/kg fenofibrate on Day 2 or 3, while 30 mg/kg Wy-14,643 administration increased expression of both genes by 1.8-fold on Day 3. In addition to previously reported gene expression changes by PPARα agonists, we found expression changes of other genes, including cis-retinol/3α-hydroxysterol short chain dehydrogenase, vanin-1, RecA-like protein, and serum amyloid A (SAA) 2. Among them, the change of SAA2 mRNA level was noteworthy; it showed a decrease to as little as one-seventh. Seven-day fenofibrate pre-treatment of mice completely inhibited the acute-phase elevation of plasma SAA concentration triggered by acetaminophen challenge. This finding suggests that fenofibrate treatment may reduce plasma SAA concentration in patients with secondary amyloidosis.

References (52)

S.M. Grundy et al.
Fibric acids: Effects on lipids and lipoprotein metabolism
Am. J. Med.
(1987)
C.R. Sirtori et al.
Effects of fibrates on serum lipids and atherosclerosis
Pharmacol. Ther.
(1988)
B. Vessby et al.
Effects of bezafibrate on the serum lipoprotein lipid and apolipoprotein composition, lipoprotein triglyceride removal capacity and the fatty acid composition of the plasma lipid esters
Atherosclerosis
(1980)
S. Haubenwallner et al.
Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: A potential physiologic basis for their mode of action
J. Lipid Res.
(1995)
B. Staels et al.
Down-regulation of hepatic lipase gene expression and activity by fenofibrate
Biochim. Biophys. Acta
(1992)
B. Staels et al.
Lecithin:Cholesterol acyltransferase gene expression is regulated in a tissue-selective manner by fibrates
J. Lipid Res.
(1992)
J.E. Manautou et al.
Protection against acetaminophen hepatotoxicity by a single dose of clofibrate: Effects on selective protein arylation and glutathione depletion
Fund. Appl. Toxicol.
(1996)
B.E. Fayos et al.
Regulation of hepatocytic glycoprotein sialylation and sialyltransferases by peroxisome proliferators
J. Biol. Chem.
(1994)
K. Tanaka et al.
Down regulation of epidermal growth factor receptors in rat hepatocytes treated with clofibric acid
Toxicol. Lett.
(1997)
A. Hermanowski-Vosatka et al.
PPARα agonists reduce 11β-hydroxysteroid dehydrogenase type 1 in the liver
Biochem. Biophys. Res. Commun.
(2000)

M. Aurrand-Lions et al.

Vanin-1, a novel GPI-linked perivascular molecule involved in thymus homing

Immunity

(1996)

G. Pitari et al.

Pantetheinase activity of membrane-bound Vanin-1: Lack of free cysteamine in tissues of Vanin-1 deficient mice

FEBS Lett.

(2000)

G.R. Haenen et al.

Effect of thiols on lipid peroxidation in rat liver microsomes

Chem.-Biol. Interact.

(1989)

E. Malle et al.

Serum amyloid A (SAA): An acute phase protein and apolipoprotein

Atherosclerosis

(1993)

M.E. Poynter et al.

Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging

J. Biol. Chem.

(1998)

J.D. Gillmore et al.

Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein

Lancet

(2001)

P.A. Todd et al.

Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia

Drugs

(1988)

J.A. Balfour et al.

Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia

Drugs

(1990)

A.P. Goldberg et al.

Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis

N. Engl. J. Med.

(1979)

F. Heller et al.

Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects

Eur. J. Clin. Pharmacol.

(1983)

B. Staels et al.

Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates

J. Clin. Invest.

(1995)

B. Staels et al.

Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat

Arterioscler. Thromb.

(1992)

B. Staels et al.

Apolipoprotein A-IV messenger ribonucleic acid abundance is regulated in a tissue-specific manner

Endocrinology

(1990)

B. Staels et al.

Perturbation of developmental gene expression in rat liver by fibric acid derivatives: Lipoprotein lipase and α-fetoprotein as models

Development

(1992)

K. Schoonjans et al.

Acyl-CoA synthetase mRNA expression is controlled by fibric-acid derivatives, feeding and liver proliferation

Eur. J. Biochem.

(1993)

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Vanin1 (VNN1) is an exogenous enzyme with pantetheinase activity that mainly exerts physiological functions through enzyme catalysis products, including pantothenic acid and cysteamine. In recent years, the crosstalk between VNN1 and metabolism and oxidative stress has attracted much attention. As a result of the ability of VNN1 to affect multiple metabolic pathways and oxidative stress to exacerbate or alleviate pathological processes, it has become a key component of disease progression. This review discusses the functions of VNN1 in glucolipid metabolism, cysteamine metabolism, and glutathione metabolism to provide perspectives on VNN1-targeted therapy for chronic diseases.
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The time and dosage of PTU and T3 used were based in previous studies [17,18]. Control mice fed LFD or HFD received saline as vehicle.Moreover, we also evaluate the impact of fenofibrate, a PPAR-alpha agonist on the small intestine of mice.For that, mice fed with LFD were once daily treated with fenofibrate from Sigma-Aldrich (100 mg/Kg) or sorbitol (vehicle) by gavage, for 12 days [19]. All mice were euthanized at six- month of age by decapitation, under isoflurane inhalation anesthesia.
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C57BL/6 male mice fed LFD or HFD diets for 12 weeks, followed by saline, PTU (antithyroid drug) or T3 treatment up to 30 days. The mice were euthanized and proximal intestine was removed to study GLUT2, GLUT5, PEPT1, FAT-CD36, FATP4, NPC1L1 and NHE3 distribution by Western blotting. Since PPAR-a is activated by fatty acids, which is abundant in the HFD, we also evaluated whether PPAR-a affects nutrients transporters. Thus, mice were treated with fenofibrate, a PPAR-a agonist.
HFD decreased GLUT2, PEPT1, FAT-CD6 and NPC1L1, but increased NHE3, while GLUT5 and FATP4 remained unaltered. THs did not alter distribution of nutrients transporters neither in LFD nor in HFD groups, but they increased villi length and depth crypt in LFD and HFD, respectively. Fenofibrate did not affect content of nutrients transporters, excluding PPAR-a involvement on the HFD-induced changes.
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Head smut of maize, which is caused by Sporisorium reilianum f. sp. zeae (Kühn), is a serious disease in maize. In order to reveal the molecular mechanism of the resistance to head smut in maize, a microarray containing ∼ 14,850 probes was used to monitor the gene expression profiles between a disease resistant near isogenic line (NIL) and a highly susceptible inbred line after S. reilianum was injected with an artificial inoculation method.
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In addition, PPARα has emerged as a crucial transcriptional regulator of numerous other metabolic processes including metabolism of glucose, cholesterol, bile acids, and amino acids [4–6]. Several different research groups have identified vanin-1 as an important PPARα-target gene [3,7–9] and showed that production of vanin-1 depends on PPARα activity [7]. However, despite the observations that vanin-1 is highly expressed in the liver as compared to other tissues [10,11], little is known about its actual role in hepatic lipid metabolism.
Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARα target gene in liver, but its function in hepatic lipid metabolism is unknown.
We investigated the regulation of vanin-1, and total vanin activity, by PPARα in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity.
Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARα activity. In addition, activation of mouse PPARα regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARα, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARα agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation.
We show that hepatic vanin-1 is under extremely sensitive regulation by PPARα and that plasma vanin activity could serve as a readout of changes in PPARα activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting.
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In adult tissues, Vnn1 is heterogeneously expressed by epithelial tissues [10] and its expression level is modulated by stress [11,12]. Microarray analyses have shown that PPARα activation lead to upregulated Vnn1 gene expression [13,14]. Using Vnn1 deficient mice, we showed that Vnn1 regulates gut inflammation [3,15].
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Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the superfamily of nuclear hormone receptors and regulate the expression of several genes involved in metabolic processes that are potentially linked to the development of some diseases such as hyperlipidemia, diabetes, and obesity. One type of PPAR, PPAR-α, is a transcription factor that regulates the metabolism of lipids, carbohydrates, and amino acids and is activated by ligands such as polyunsaturated fatty acids and drugs used to treat dyslipidemias. There is evidence that genetic variants within the PPARα gene have been associated with a risk of the development of dyslipidemia and cardiovascular disease by influencing fasting and postprandial lipid concentrations; the gene variants have also been associated with an acceleration of the progression of type 2 diabetes. The interactions between genetic PPARα variants and the response to dietary factors will help to identify individuals or populations who can benefit from specific dietary recommendations. Interestingly, certain nutritional conditions, such as the prolonged consumption of a protein-restricted diet, can produce long-lasting effects on PPARα gene expression through modifications in the methylation of a specific locus surrounding the PPARα gene. Thus, this review underlines our current knowledge about the important role of PPAR-α as a mediator of the metabolic response to nutritional and environmental factors.

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Regular ArticleMicroarray Analysis of Gene Expression Changes in Mouse Liver Induced by Peroxisome Proliferator- Activated Receptor α Agonists

Abstract

Am. J. Med.

Pharmacol. Ther.

Atherosclerosis

J. Lipid Res.

Biochim. Biophys. Acta

J. Lipid Res.

Fund. Appl. Toxicol.

J. Biol. Chem.

Toxicol. Lett.

Biochem. Biophys. Res. Commun.

Immunity

FEBS Lett.

Chem.-Biol. Interact.

Atherosclerosis

J. Biol. Chem.

Lancet

Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia

Drugs

Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia

Drugs

Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis

N. Engl. J. Med.

Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects

Eur. J. Clin. Pharmacol.

Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates

J. Clin. Invest.

Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat

Arterioscler. Thromb.

Apolipoprotein A-IV messenger ribonucleic acid abundance is regulated in a tissue-specific manner

Endocrinology

Perturbation of developmental gene expression in rat liver by fibric acid derivatives: Lipoprotein lipase and α-fetoprotein as models

Development

Acyl-CoA synthetase mRNA expression is controlled by fibric-acid derivatives, feeding and liver proliferation

Eur. J. Biochem.

Regular Article
Microarray Analysis of Gene Expression Changes in Mouse Liver Induced by Peroxisome Proliferator- Activated Receptor α Agonists