Peroxisome Proliferator-activated Receptor α Inhibits Hepatic S14 Gene Transcription

Ren, Bing; Thelen, Annette; Jump, Donald Β.

doi:10.1074/jbc.271.29.17167

Cited by 80 publications

(35 citation statements)

References 56 publications

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“…Increasing the dose of 20:5n-3 significantly induced PPAR␣ activity (ϳ8-fold at 1 mM), whereas a comparable dose of 18:1n-9 had no effect. These studies confirm previous findings on the differen-tial effects of these putative ligands on PPAR␣ activity in primary hepatocytes (15,16). These studies also indicate that the difference in effect of these two fatty acids on PPAR␣ activity cannot be explained on the basis of treatment dose alone.…”

Section: Effect Of Unsaturated Fatty Acids On Ppar␣ Activity In Pri-supporting

confidence: 92%

“…mRNA AOX or mRNA CYP4A (Figs. 1 and 4) (15,16). In contrast, 20:5n-3 and 22:5n-3 are very low abundance fatty acids in primary hepatocytes (Fig.…”

Section: -Carbon N3-pufa Regulation Of Ppar␣-becausementioning

confidence: 99%

“…PPAR␣-regulated transcript (15,16). Addition of 20:5n-3 to primary hepatocytes induced a prompt rise (2-fold within 6 h) in mRNA CYP4A , followed by a 50% drop by 24 h (Fig.…”

Section: Mass Of 20:5n-3 In the Nefa Pool And Not The Formation Of Ementioning

confidence: 99%

“…In vivo feeding studies have shown that when calories supplied as saturated and monounsaturated fat are Յ20% of total calories, hepatic PPAR␣-regulated transcripts, like acyl CoA oxidase and cytochrome P-450 -4A (CYP4A) are marginally affected (15,16). Substituting fish oil, a rich source of 20-and 22-carbon N3-PUFA, leads to a pronounced induction of enzymes involved in lipid oxidation.…”

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confidence: 99%

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Unsaturated Fatty Acid Regulation of Peroxisome Proliferator-activated Receptor α Activity in Rat Primary Hepatoctes

Pawar

Jump

2003

Journal of Biological Chemistry

Self Cite

184

151

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Peroxisome proliferator-activated receptors (PPARs ␣, ␤, ␥1, and ␥2) are widely regarded as monitors of intracellular nonesterified fatty acid (NEFA) levels. As such, fatty acid binding to PPAR leads to changes in the transcription of many genes involved in lipid metabolism and storage. Although the composition of the intracellular NEFA pool is likely an important factor controlling PPAR activity, little information is available on factors affecting its composition. Accordingly, we have examined the effects of exogenous fatty acids on PPAR␣ activity and NEFA pool composition in rat primary hepatocytes. Prior to the addition of fatty acids to primary hepatocytes, nonesterified unsaturated fatty acid levels are very low, representing <0.5% of the total fatty acid in the cell. The relative abundance of putative PPAR␣ ligands in the NEFA pool is 20:4n-6 ‫؍‬ 18:2n-6 ‫؍‬ 18:1n-9 > 22:6n-3 > 18:3n-3/6 ‫؍‬ 20:5n-3. Of these fatty acids, only 20:5n-3 and 22:6n-3 consistently induced PPAR␣ activity. Metabolic labeling of primary hepatocytes indicated that both 14 C-18:1n-9 and 14 C-20:5n-3 are rapidly assimilated into neutral and polar lipids. Although the addition of 18:1n-9 had no effect on NEFA pool composition, 20:5n-3 mass increased >15-fold within 90 min. Changes in NEFA pool 20:5n-3 mass correlated with dynamic changes in the PPAR␣-regulated transcript mRNA CYP4A . Metabolic labeling also indicated that a significant fraction of 14 C-20:5n-3 was elongated to 22:5n-3. Cells treated with 22:5n-3 or 22:6n-3 led to a significant accumulation of 20:5n-3 in the NEFA pool through a process that requires peroxisomal ␤-oxidation and fatty acyl CoA thioesterase activity. Further analyses suggest that 20:5n-3 and 22:6n-3, but not 22:5n-3, are active ligands for PPAR␣. These studies suggest that basal fatty acid levels in the NEFA pool coupled with rates of fatty acid esterification, elongation, desaturation, peroxisomal ␤-oxidation, and fatty acyl thioestease activity are important determinants controlling NEFA pool composition and PPAR␣ activity.

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Section: Effect Of Unsaturated Fatty Acids On Ppar␣ Activity In Pri-supporting

confidence: 92%

“…mRNA AOX or mRNA CYP4A (Figs. 1 and 4) (15,16). In contrast, 20:5n-3 and 22:5n-3 are very low abundance fatty acids in primary hepatocytes (Fig.…”

Section: -Carbon N3-pufa Regulation Of Ppar␣-becausementioning

confidence: 99%

“…PPAR␣-regulated transcript (15,16). Addition of 20:5n-3 to primary hepatocytes induced a prompt rise (2-fold within 6 h) in mRNA CYP4A , followed by a 50% drop by 24 h (Fig.…”

Section: Mass Of 20:5n-3 In the Nefa Pool And Not The Formation Of Ementioning

confidence: 99%

mentioning

confidence: 99%

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Unsaturated Fatty Acid Regulation of Peroxisome Proliferator-activated Receptor α Activity in Rat Primary Hepatoctes

Pawar

Jump

2003

Journal of Biological Chemistry

Self Cite

184

151

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“…In addition, certain of these genes have been shown to carry both TREs and PPREs (50,51). Cross-talk between PPAR and TR may furthermore occur by competition for binding to DNA (52,53) or for the common heterodimeric partner RXR (53)(54)(55)(56), or by formation of PPAR:TR heterodimers, as has been suggested by one report (57). Our data identifying Rev-erb␣ as a fibrate target gene suggests another layer of cross-talk between the TR and PPAR signaling pathways.…”

Section: Discussionmentioning

confidence: 87%

The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates

Vu‐Dac¹,

Chopin-Delannoy²,

Gervois³

et al. 1998

Journal of Biological Chemistry

281

174

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Fibrates are widely used hypolipidemic drugs which activate the nuclear peroxisome proliferator-activated receptor (PPAR) ␣ and thereby alter the transcription of genes controlling lipoprotein metabolism. Fibrates influence plasma high density lipoprotein and its major protein, apolipoprotein (apo) A-I, in an opposite manner in man (increase) versus rodents (decrease). In the present study we studied the molecular mechanisms of this species-specific regulation of apoA-I expression by fibrates. In primary rat and human hepatocytes fenofibric acid, respectively, decreased and increased apoA-I mRNA levels. The absence of induction of rat apoA-I gene expression by fibrates is due to 3 nucleotide differences between the rat and the human apoA-I promoter A site, rendering a positive PPAR-response element in the human apoA-I promoter nonfunctional in rats. In contrast, rat, but not human, apoA-I transcription is repressed by the nuclear receptor Rev-erb␣, which binds to a negative response element adjacent to the TATA box of the rat apoA-I promoter. In rats fibrates increase liver Rev-erb␣ mRNA levels >10-fold. In conclusion, the opposite regulation of rat and human apoA-I gene expression by fibrates is linked to differences in cis-elements in their respective promoters leading to repression by Rev-erb␣ of rat apoA-I and activation by PPAR␣ of human apoA-I. Finally, Rev-erb␣ is identified as a novel fibrate target gene, suggesting a role for this nuclear receptor in lipid and lipoprotein metabolism.

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Glucocorticoids repress induction by thiazolidinediones, fibrates, and fatty acids of phosphoenolpyruvate carboxykinase gene expression in adipocytes

Glorian¹,

Franckhauser²,

Robin³

et al. 1998

J. Cell. Biochem.

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Phosphoenolpyruvate carboxykinase (PEPCK) exerts a glyceroneogenic function in adipocytes in which transcription of its gene is increased by unsaturated fatty acids and fibrates. We used cultured rat adipose tissue fragments and 3T3-F442A adipocytes to show that the antidiabetic thiazolidinedione BRL 49653, a ligand and an activator of the gamma isoform of peroxisome proliferator activated receptors (PPARgamma), is a potent inducer of PEPCK mRNA. In 3T3-F442A adipocytes, the effect of BRL 49653 is rapid and concentration dependent, with a maximum reached at 1 microM and a half-maximum at 10-100 nM. PEPCK mRNA is similarly induced by the natural ligand of PPARgamma, the 15-deoxy-delta(12-14) prostaglandin J2. These observations strongly suggest that PPARgamma is a primary regulator of PEPCK gene expression in adipocytes. Dexamethasone at 10 nM repress induction of PEPCK mRNA by 1 microM BRL 49653, 0.32 mM oleate, or 1 mM clofibrate, in a cycloheximide-independent manner. The antiglucocorticoid RU 38486 prevents dexamethasone action, demonstrating involvement of the glucocorticoid receptor. Stable transfectants of 3T3-F442A adipocytes bearing -2100 to +69 base pairs of the PEPCK gene promoter fused to the chloramphenicol acetyltransferase (CAT) gene respond to 1 microM BRL 49653 or 1 mM clofibrate by a large increase in CAT activity, which is prevented by the simultaneous addition of 10 nM dexamethasone. Hence, in adipocytes, glucocorticoids act directly through the 5'-flanking region of the PEPCK gene to repress, in a dominant fashion, the stimulation of PEPCK gene transcription by thiazolidinediones and fibrates.

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Peroxisome Proliferator-activated Receptor α Inhibits Hepatic S14 Gene Transcription

Cited by 80 publications

References 56 publications

Unsaturated Fatty Acid Regulation of Peroxisome Proliferator-activated Receptor α Activity in Rat Primary Hepatoctes

Unsaturated Fatty Acid Regulation of Peroxisome Proliferator-activated Receptor α Activity in Rat Primary Hepatoctes

The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates

Glucocorticoids repress induction by thiazolidinediones, fibrates, and fatty acids of phosphoenolpyruvate carboxykinase gene expression in adipocytes

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