Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes

Kroetz, Deanna L.; Yook, Philip; Costet, Phillipe; Bianchi, P; Pineau, Thierry

doi:10.1074/jbc.273.47.31581

Cited by 193 publications

(158 citation statements)

References 49 publications

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“…As the corollary to this function, PPAR␣ Ϫ/Ϫ mice develop hepatic steatosis and hypertriglyceridemia and are unable to increase ketogenesis in response to circumstances that require fatty acids as the major fuel source, such as fasting or diabetes. 14,40 In this study, PPAR␣ Ϫ/Ϫ mice fed a high-fat but otherwise nutritionally adequate diet developed severe hepatic steatosis and in some cases mild hepatic necroinflammatory changes. It seems likely that lipid overload occurs to a threshold for progression to steatohepatitis in the absence of other aggravating factors so that PPAR␣-dependent intrahepatic fatty acid combustion reduces the susceptibility to steatohepatitis as well as steatosis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to LFABP and the enzymatic pathways involved in fatty acid turnover studied here (peroxisomal ACO, BIEN, KT, and Cyp4a enzymes), PPAR␣ also regulates the expression of mitochondrial ␤-oxidation enzymes and proteins involved in fatty acid trafficking including fatty acid transport protein and apolipoproteins A-I and A-II. 14,38,39 The main physiologic function of the PPAR␣ system in rodents, appears to be coordinating the switch to utilize fatty acids as the main hepatic fuel source. As the corollary to this function, PPAR␣ Ϫ/Ϫ mice develop hepatic steatosis and hypertriglyceridemia and are unable to increase ketogenesis in response to circumstances that require fatty acids as the major fuel source, such as fasting or diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…11 Cyp4a and ACO are among several genes involved in fatty acid turnover that are regulated by the ligandactivated transcription factor, peroxisome proliferatoractivated receptor ␣ (PPAR␣). [12][13][14] Unmetabolized fatty acids that accumulate in ACO Ϫ/Ϫ mice are thought to act as ligands of PPAR␣ thereby up-regulating Cyp4a and other PPAR␣ target genes. The potential importance of such induction of Cyp4a and products of lipoperoxides for the pathogenesis of steatohepatitis is lent credence by the observation that ACO/PPAR␣ double knockout mice develop only mild steatohepatitis.…”

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Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

et al. 2003

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We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPAR␣ ؊/؊ mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPAR␣ ؊/؊ mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPAR␣ agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal ␤-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPAR␣ ؊/؊ mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPAR␣ activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis. (HEPATOLOGY 2003;38:123-132.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

et al. 2003

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“…Cyp4a isoforms are increased in rodent livers and kidneys by peroxisome proliferators, physiologic states such as diabetes and starvation, and inflammation and infection. 43,44 In addition to their roles in the metabolism of fatty acids and prostaglandins, Cyp4a enzymes catalyze the synthesis of eicosanoids. Most notably, Cyp4a enzymes catalyze the -and 1-hydroxylation of fatty acids, including arachadonic acid, as well as arachadonic acid epoxidations.…”

Section: Discussionmentioning

confidence: 99%

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

et al. 2002

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Peroxisome proliferator chemicals, acting via the peroxisome proliferator-activated receptor-␣ (Ppar␣), are potent hepatic mitogens and carcinogens in mice and rats. To test whether Ppar␣ is required for hepatic growth in response to other stimuli, we studied liver regeneration and hepatic gene expression following partial hepatectomy (PH) of wild-type and Ppar␣-null mice. Ppar␣-null mice had a 12-to 24-hour delay in liver regeneration associated with a delayed onset and lower peak magnitude of hepatocellular DNA synthesis. Furthermore, these mice had a 24-hour lag in the hepatic expression of the G 1 /S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1␤ cytokine gene. Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Ppar␣-null mice, after acute exposure to the potent Ppar␣ agonist Wy-14,643, indicating a role for Ppar␣ in regulating the expression of these genes. Expression of the fatty acid -hydroxylase gene Cyp4a14, a commonly used indicator gene for Ppar␣ activation, was strongly induced in wild-type mice after hepatectomy, suggesting that altered hepatocyte lipid processing may also contribute to the impaired regeneration in mice lacking the Ppar␣ gene. In conclusion, liver regeneration in Ppar␣-null mice is transiently impaired and is associated with altered expression of genes involved in cell cycle control, cytokine signaling, and fat metabolism. (HEPATOLOGY 2002;36:544-554.) P eroxisome proliferator (PP) xenobiotics are potent hepatic mitogens and carcinogens in mice and rats. 1 Increases in hepatocyte replication and tumor formation after PP exposure require activation of the peroxisome proliferator-activated receptor-␣ (Ppar␣). 2 Many transcriptional targets of Ppar␣ have been identified, but none have direct roles in regulating cell proliferation or apoptosis. One of the most effective models for studying hepatocellular proliferation is liver regeneration following hepatocellular loss because of partial hepatectomy (PH) or chemical damage. 3 In the original technique for PH described by Higgins and Anderson in 1931, 4 resection of 70% of the hepatic mass of a rat results in 95% of the remaining hepatocytes rapidly entering the cell cycle. DNA synthesis follows about 12 to 14 hours after resection and reaches a maximum activation at 24 hours. These events occur about 20 hours later in mice. The original mass of the liver is restored within 7 days, with most of the recovery occurring by 3 days. 4 The signals that stimulate and maintain this process are not entirely clear but include the transcriptional activation of several groups of genes in a distinct temporal order. 3,[5][6][7] First, hepatocytes must be primed, presumably by cytokines, to respond to various growth factors. After priming, transition from G 0 to G 1 phases of the cell cycle requires induction of immediate-early class genes, which begins at about 30 minutes post-PH and lasts for about 4 hours. Progression of hepatocytes in vivo through late G 1 phase requires gr...

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“…On the other hand, constitutive peroxisomal ␤-oxidation is quite independent of PPAR␣, but the receptor is required for induction of this system by peroxisome proliferators (9). Recent observations (11)(12)(13)(14) point out the critical importance of PPAR␣ in determining the severity of hepatic steatosis in fasting, in diabetes (14), and in animals fed a high fat diet (11).…”

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confidence: 99%

Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice

Fischer

You

Matsumoto

et al. 2003

Journal of Biological Chemistry

273

196

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Proper function of the peroxisome proliferator-activated receptor ␣ (PPAR␣) is essential for the regulation of hepatic fatty acid metabolism. Fatty acid levels are increased in liver during the metabolism of ethanol and should activate PPAR␣. However, recent in vitro data showed that ethanol metabolism inhibited the function of PPAR␣. We now report that ethanol feeding impairs fatty acid catabolism in the liver in part via blocking PPAR␣-mediated responses in C57BL/6J mice. Ethanol feeding decreased PPAR␣/retinoid X receptor ␣ binding in electrophoretic mobility shift assay of liver nuclear extracts. mRNAs for PPAR-regulated genes were reduced (long chain and medium chain acyl-CoA dehydrogenases) or failed to be induced (acyl-CoA oxidase, liver carnitine palmitoyl-CoA transferase, very long chain acyl-CoA synthetase, very long chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals, and ethanol feeding did not increase the rate of fatty acid ␤-oxidation. Wy14,643, a PPAR␣ agonist, restored the DNA binding activity of PPAR␣/retinoid X receptor ␣, induced mRNA levels of PPAR␣ target genes, stimulated the rate of fatty acid ␤-oxidation, and prevented fatty liver in ethanol-fed animals. Impairment of PPAR␣ function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by Wy14,643.

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Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes

Cited by 193 publications

References 49 publications

Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice

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