Expression of peroxisome proliferator-activated receptor α, and PPARα regulated genes in spontaneously developed hepatocellular carcinomas in fatty acyl-CoA oxidase null mice

The interrelationship between insulin and leptin resistance in young Fischer 344 (F344) rats was studied. Young F344 and Sprague-Dawley (SD) rats were fed regular chow. F344 animals had two- to threefold higher insulin and triglyceride concentrations and increased stores of triglycerides within liver and muscle. F344 animals gained more body fat. Both acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase I gene expression were 20–50% less in F344 animals than in age-matched SD animals. Peroxisome proliferator-activated receptor-α gene expression was reduced in 70-day-old F344 animals. Finally, resistin gene expression was similar in 70-day-old SD and F344 animals. Resistin gene expression increased fivefold in F344 animals and twofold in SD animals from 70 to 130 days, without a change in insulin sensitivity. We conclude that young F344 animals have both insulin and leptin resistance, which may lead to diminished fatty oxidation and accumulation of triglycerides in insulin-sensitive target tissues. We did not detect a role for resistin in the etiology of insulin resistance in F344 animals.

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Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01344.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. H2480-H2497 ◽

Cited By ~ 66

Author(s):

David J. Durgan ◽

Justin K. Smith ◽

Margaret A. Hotze ◽

Oluwaseun Egbejimi ◽

Karalyn D. Cuthbert ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acyl ◽

Null Mouse ◽

Peroxisome Proliferator ◽

Futile Cycle ◽

Peroxisome Proliferator Activated Receptor ◽

Rat Cardiomyocytes ◽

Adult Rat ◽

Chain Acyl ◽

Long Chain

The molecular mechanism(s) responsible for channeling long-chain fatty acids (LCFAs) into oxidative versus nonoxidative pathways is (are) poorly understood in the heart. Intracellular LCFAs are converted to long-chain fatty acyl-CoAs (LCFA-CoAs) by a family of long-chain acyl-CoA synthetases (ACSLs). Cytosolic thioesterase 1 (CTE1) hydrolyzes cytosolic LCFA-CoAs to LCFAs, generating a potential futile cycle at the expense of ATP utilization. We hypothesized that ACSL isoforms and CTE1 are differentially regulated in the heart during physiological and pathophysiological conditions. Using quantitative RT-PCR, we report that the five known acsl isoforms ( acsl1, acsl3, acsl4, acsl5, and acsl6) and cte1 are expressed in whole rat and mouse hearts, as well as adult rat cardiomyocytes (ARCs). Streptozotocin-induced insulin-dependent diabetes (4 wk) and fasting (≤24 h) both dramatically induced cte1 and repressed acsl6 mRNA, with no significant effects on the other acsl isoforms. In contrast, high-fat feeding (4 wk) induced cte1 without affecting expression of the acsl isoforms in the heart. Investigation into the mechanism(s) responsible for these transcriptional changes uncovered roles for peroxisome proliferator-activated receptor-α (PPARα) and insulin as regulators of specific acsl isoforms and cte1 in the heart. Culturing ARCs with oleate (0.1–0.4 mM) or the PPARα agonists WY-14643 (1 μM) and fenofibrate (10 μM) consistently induced acsl1 and cte1. Conversely, PPARα null mouse hearts exhibited decreased acsl1 and cte1 expression. Culturing ARCs with insulin (10 nM) induced acsl6, whereas specific loss of insulin signaling within the heart (cardiac-specific insulin receptor knockout mice) caused decreased acsl6 expression. Our data expose differential regulation of acsl isoforms and cte1 in the heart, where acsl1 and cte1 are PPARα-regulated genes, whereas acsl6 is an insulin-regulated gene.

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Molecular profiling of hepatocellular carcinomas developing spontaneously in acyl-CoA oxidase deficient mice: comparison with liver tumors induced in wild-type mice by a peroxisome proliferator and a genotoxic carcinogen

Carcinogenesis ◽

10.1093/carcin/bgg040 ◽

2003 ◽

Vol 24 (5) ◽

pp. 975-984 ◽

Cited By ~ 46

Author(s):

K. Meyer

Keyword(s):

Liver Tumors ◽

Molecular Profiling ◽

Peroxisome Proliferator ◽

Wild Type ◽

Genotoxic Carcinogen ◽

Hepatocellular Carcinomas ◽

Acyl Coa Oxidase ◽

Deficient Mice

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Increase in hepatic expression of SREBP-2 by gemfibrozil administration to rats 1 1Abbreviations: ACO, acyl-CoA oxidase; Apo, apolipoprotein; APRT, adenosyl phosphoribosyl transferase; CT, CTP:phosphocholine cytidylyl transferase; HDL, high-density lipoprotein; HMG-CoA Rd, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; LDL, low-density lipoprotein; PAP, phosphatidate phosphohydrolase; PPARα, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element binding protein; and VLDL, very-low-density lipoprotein.

Biochemical Pharmacology ◽

10.1016/s0006-2952(01)00701-8 ◽

2001 ◽

Vol 62 (6) ◽

pp. 803-809 ◽

Cited By ~ 14

Author(s):

Núria Roglans ◽

Cristina Peris ◽

Juan C. Verd ◽

Marta Alegret ◽

Manuel Vázquez ◽

...

Keyword(s):

Regulatory Element ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Peroxisome Proliferator ◽

Low Density ◽

Peroxisome Proliferator Activated Receptor ◽

Hepatic Expression ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Acyl Coa Oxidase

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Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00414.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. E395-E401 ◽

Cited By ~ 90

Author(s):

Susanne Neschen ◽

Irene Moore ◽

Werner Regittnig ◽

Chun Li Yu ◽

Yanlin Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Fish Oil ◽

Oxidative Capacity ◽

Fatty Acyl ◽

Control Fish ◽

Safflower Oil ◽

Peroxisome Proliferator ◽

Hepatic Triglyceride ◽

Peroxisome Proliferator Activated Receptor ◽

Ceramide Content

To examine the mechanism by which fish oil protects against fat-induced insulin resistance, we studied the effects of control, fish oil, and safflower oil diets on peroxisomal content, fatty acyl-CoA, diacylglycerol, and ceramide content in rat liver and muscle. We found that, in contrast to control and safflower oil-fed rats, fish oil feeding induced a 150% increase in the abundance of peroxisomal acyl-CoA oxidase and 3-ketoacyl-CoA thiolase in liver but lacked similar effects in muscle. This was paralleled by an almost twofold increase in hepatic peroxisome content (both P < 0.002 vs. control and safflower). These changes in the fish oil-fed rats were associated with a more than twofold lower hepatic triglyceride/diacylglycerol, as well as intramuscular triglyceride/fatty acyl-CoA, content. In conclusion, these data strongly support the hypothesis that n-3 fatty acids protect against fat-induced insulin resistance by serving as peroxisome proliferator-activated receptor-α ligands and thereby induce hepatic, but not intramuscular, peroxisome proliferation. In turn, an increased hepatic β-oxidative capacity results in lower hepatic triglyceride/diacylglycerol and intramyocellular triglyceride/fatty acyl-CoA content.

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