Species differences in induction of hepatic enzymes by BM 17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPARα)

Meyer, Kirstin; Völkl, Alfred; Endele, R.; Kühnle, H.F.; Pill, Johannes

doi:10.1007/s002040050633

Cited by 26 publications

(17 citation statements)

References 37 publications

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“…ACC, acetyl-CoA carboxylase; ACS, acyl-CoA synthetase; ␤ -Ox, ␤ -oxidation; CPT-1, carnitine palmitoyltransferase-1; G6Pase, glucose 6-phosphatase; HMGR, HMG-CoA reductase; PEPCK, phosphoenolpyruvate carboxykinase; TCA, tricarboxylic acid. compounds (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92) and provide further clarity into their respective mechanisms ( 84,91,(93)(94)(95)(96)(97)(98)(99)(100).…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

Pinkosky

Filippov

Srivastava

et al. 2013

Journal of Lipid Research

194

153

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This article is available online at http://www.jlr.org Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the Western world ( 1 ). Elevated levels of LDL-cholesterol (LDL-C) have consistently shown a positive association with the development of CVD, justifying the current therapeutic strategies to prevent CVD primarily by the use of statins. Members of this drug class inhibit HMG-CoA reductase (HMGR), the rate-limiting enzyme for de novo cholesterol synthesis, thereby leading to decreased LDL-C ( 2-4 ). While the benefi ts of statins have been documented ( 2 ), many individuals on statin therapy still remain at a higher risk of developing CVD. It is possible this residual risk is a result of other metabolic syndrome (MetS) risk factors characterized by dyslipidemia and insulin resistance and is also in part due to statin intolerance ( 5-7 ) and noncompliance often related to statininduced myalgia ( 8, 9 ). Statins are effective at decreasing LDL-C and CVD; however, frequent muscle-related side effects limit dosage and impede maximal risk reduction in dyslipidemic patients ( 10 ). Furthermore, recent evidence suggests that high-dose statins may increase the risk of developing type 2 diabetes (T2D) ( 11 ), further justifying the need for alternative therapeutic interventions that have statin-like effects for lowering LDL-C and are designed to Abstract ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid ␤ -oxidation. However, the molecular mechanism(s) mediating these activities remained undefi ned.

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Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

Pinkosky

Filippov

Srivastava

et al. 2013

Journal of Lipid Research

194

153

View full text Add to dashboard Cite

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“…11), it is interesting to note that the PPAR␥ ligand troglitazone (at very high concentrations that may cause PPAR␣ activation) reverses the secretory and lipid metabolism alterations of the ␤-cell in ZDF rats (6). In addition, treatments of yellow KK mice with BM17.0744, a new PPAR␣ agonist, results in an amelioration of the diabetic status and dyslipidemia (57).…”

Section: Discussionmentioning

confidence: 99%

Glucose Down-regulates the Expression of the Peroxisome Proliferator-activated Receptor-α Gene in the Pancreatic β-Cell

Roduit

Morin

Massé

et al. 2000

Journal of Biological Chemistry

153

118

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To better understand the action of glucose on fatty acid metabolism in the ␤-cell and the link between chronically elevated glucose or fatty acids and ␤-cell decompensation in adipogenic diabetes, we investigated whether glucose regulates peroxisomal proliferator-activated receptor (PPAR) gene expression in the ␤-cell. Islets or INS(832/13) ␤-cells exposed to high glucose show a 60 -80% reduction in PPAR␣ mRNA expression. Oleate, either in the absence or presence of glucose, has no effect. The action of glucose is dose-dependent in the 6 -20 mM range and maximal after 6 h. Glucose also causes quantitatively similar reductions in PPAR␣ protein and DNA binding activity of this transcription factor. The effect of glucose is blocked by the glucokinase inhibitor mannoheptulose, is partially mimicked by 2-deoxyglucose, and is not blocked by the 3-O-methyl or the 6-deoxy analogues of the sugar that are not phosphorylated. Chronic elevated glucose reduces the expression levels of the PPAR target genes, uncoupling protein 2 and acyl-CoA oxidase, which are involved in fat oxidation and lipid detoxification. A 3-day exposure of INS-1 cells to elevated glucose results in a permanent rise in malonyl-CoA, the inhibition of fat oxidation, and the promotion of fatty acid esterification processes and causes elevated insulin secretion at low glucose. The results suggest that a reduction in PPAR␣ gene expression together with a rise in malonyl-CoA plays a role in the coordinated adaptation of ␤-cell glucose and lipid metabolism to hyperglycemia and may be implicated in the mechanism of ␤-cell "glucolipotoxicity."

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“…However, PPAR-␣-induced hepatomegaly-presumably by promoting peroxisome proliferation-is thought to be species-specific for rodents (39). In fact, the fibrate class of PPAR-␣ agonists was safely used in humans to treat hypertriglyceridemia, and no hepatomegaly was reported (11).…”

Section: The Role Of Lipids In Ppar's Action On Insulin Sensitivitymentioning

confidence: 99%

Peroxisome Proliferator—Activated Receptor (PPAR)-αActivation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat—Fed Rats

et al. 2001

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Peroxisome proliferator-activated receptor (PPAR)-␣ agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-␣ activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-␥ activation. Threeweek high fat-fed male Wistar rats were untreated or treated with the specific PPAR-␣ agonist WY14643 or the PPAR-␥ agonist pioglitazone (both 3 mg · kg -1 · day -1 ) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced wholebody insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulinmediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-␣ and PPAR-␥ activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation. Diabetes 50:411-417, 2001

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Species differences in induction of hepatic enzymes by BM 17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPARα)

Cited by 26 publications

References 37 publications

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

Glucose Down-regulates the Expression of the Peroxisome Proliferator-activated Receptor-α Gene in the Pancreatic β-Cell

Peroxisome Proliferator—Activated Receptor (PPAR)-αActivation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat—Fed Rats

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