Leone, T.C., Weinheimer, C.J. & Kelly, D.P. A critical role for the peroxisome proliferator-activated receptor (PPAR) in the cellular fasting response: the PPAR-null mouse as a model of fatty acid oxidation disorders. Proc. Natl. Acad. Sci. USA 96, 7473-7478

Washington University in St. Louis, San Luis, Missouri, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/1999; 96(13):7473-8. DOI: 10.1073/pnas.96.13.7473
Source: PubMed


We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor alpha (PPARalpha), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARalpha (PPARalpha-/-), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARalpha+/+ mice, fasting induced the hepatic and cardiac expression of PPARalpha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARalpha target genes was not induced by fasting in PPARalpha-/- mice. These results define a critical role for PPARalpha in a transcriptional regulatory response to fasting and identify the PPARalpha-/- mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.

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    • "As expected (Ryu et al. 2005; Leone et al. 1999; Narayan et al. 2014), fasting more than tripled the total hepatic content of TAG from 13.41 ± 3.42 lg fatty acid/mg liver in ad libitum fed mice to 44.53 ± 9.52 lg fatty acid/mg liver in fasted mice (Supplementary Table 3). As a result, the total concentration of all major fatty acid classes and most individual fatty acid species also increased. "
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    ABSTRACT: We investigated the effect of short-term fasting on coordinate changes in the fatty acid composition of adipose triacylglycerol (TAG), serum non-esterified fatty acids (NEFA), liver TAG, and serum TAG and phospholipids in mice fed ad libitum or fasted for 16 h overnight. In contrast to previous reports under conditions of maximal lipolysis, adipose tissue TAG was not preferentially depleted of n-3 PUFA or any specific fatty acids, nor were there any striking changes in the serum NEFA composition. Short-term fasting did, however, increase the hepatic proportion of n-3 PUFA, and almost all individual species of n-3 PUFA showed relative and absolute increases. The relative proportion of n-6 PUFA in liver TAG also increased but to a lesser extent, resulting in a significant decrease in the n-6:n-3 PUFA ratio (from 14.3 ± 2.54 to 9.6 ± 1.20), while the proportion of MUFA decreased significantly and SFA proportion did not change. Examination of genes involved in PUFA synthesis suggested that hepatic changes in the elongation and desaturation of precursor lipids could not explain this effect. Rather, an increase in the expression of fatty acid transporters specific for 22:6n-3 and other long-chain n-3 and n-6 PUFA likely mediated the observed hepatic enrichment. Analysis of serum phospholipids indicated a specific increase in the concentration of 22:6n-3 and 16:0, suggesting increased specific synthesis of DHA-enriched phospholipid by the liver for recirculation. Given the importance of blood phospholipid in distributing DHA to neural tissue, these findings have implications for understanding the adipose-liver-brain axis in n-3 PUFA metabolism.
    Genes & Nutrition 11/2015; 10(6). DOI:10.1007/s12263-015-0490-2 · 2.79 Impact Factor
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    • "To investigate whether this hypothesis is true, PPARí µí»¼ receptor null mice (PPARí µí»¼-KO) were used. PPARí µí»¼-KO mice are known to be susceptible to fasting induced hepatic steatosis [28] [29]; therefore before the sacrifice, mice were not fasted. Animals were divided into 2 groups, one control fed normal chow and the treatment group fed diet supplemented with 0.0025% GW501516 (w/w). "
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    ABSTRACT: Peroxisome proliferator activated receptors alpha (PPARí µí»¼) and delta (PPARí µí»¿) belong to the nuclear receptor superfamily. PPARí µí»¼ is a target of well established lipid-lowering drugs. PPARí µí»¿ (also known as PPARí µí»½/í µí»¿) has been investigated as a promising antidiabetic drug target; however, the evidence in the literature on PPARí µí»¿ effect on hepatic lipid metabolism is inconsistent. Mice conditionally expressing human PPARí µí»¿ demonstrated pronounced weight loss and promoted hepatic steatosis when treated with GW501516 (PPARí µí»¿-agonist) when compared to wild type mice. This effect was completely absent in mice with either a dominant negative form of PPARí µí»¿ or deletion of the DNA binding domain of PPARí µí»¿. This confirmed the absolute requirement for PPARí µí»¿ in the physiological actions of GW501516 and confirmed the potential utility against the human form of this receptor. Surprisingly the genetic deletion of PPARí µí»¼ also abrogated the effect of GW501516 in terms of both weight loss and hepatic lipid accumulation. Also the levels of the PPARí µí»¼ endogenous agonist 16:0/18:1-GPC were shown to be modulated by PPARí µí»¿ in wild type mice. Our results show that both PPARí µí»¿ and PPARí µí»¼ receptors are essential for GW501516-driven adipose tissue reduction and subsequently hepatic steatosis, with PPARí µí»¼ working downstream of PPARí µí»¿.
    PPAR Research 10/2015; 2015(1). DOI:10.1155/2015/927057 · 1.64 Impact Factor
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    • "pparí µí»¼ activation promotes FA oxidation, ketone body synthesis, and glucose sparing. Disabling the pparí µí»¼ gene is known to increase hepatic triglyceride accumulation, especially under fasting conditions [38] [39] [40]. Pharmacological activation of pparí µí»¼ has been shown to lower hepatic triglyceride levels and to effectively attenuate steatohepatitis [12] [39] [41]. "
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    ABSTRACT: The objective of this study was to investigate the effects of iron dextran on lipid metabolism and to determine the involvement of oxidative stress. Fischer rats were divided into two groups: the standard group (S), which was fed the AIN-93M diet, and the standard plus iron group (SI), which was fed the same diet but also received iron dextran injections. Serum cholesterol and triacylglycerol levels were higher in the SI group than in the S group. Iron dextran was associated with decreased mRNA levels of pparα, and its downstream gene cpt1a, which is involved in lipid oxidation. Iron dextran also increased mRNA levels of apoB-100, MTP, and L-FABP indicating alterations in lipid secretion. Carbonyl protein and TBARS were consistently higher in the liver of the iron-treated rats. Moreover, a significant positive correlation was found between oxidative stress products, lfabp expression, and iron stores. In addition, a negative correlation was found between pparα expression, TBARS, carbonyl protein, and iron stores. In conclusion, our results suggest that the increase observed in the transport of lipids in the bloodstream and the decreased fatty acid oxidation in rats, which was promoted by iron dextran, might be attributed to increased oxidative stress.
    01/2015; 2015:1-9. DOI:10.1155/2015/272617
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