Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.
The expression of several genes involved in intra-and extracellular lipid metabolism, notably those involved in peroxisomal and mitochondrial -oxidation, is mediated by ligand-activated receptors, collectively referred to as peroxisome proliferator-activated receptors (PPARs). To gain more insight into the control of expression of carnitine palmitoyltransferase (CPT) genes, which are regulated by fatty acids, we have examined the transcriptional regulation of the human MCPT I gene. We have cloned by polymerase chain reaction the 5-flanking region of this gene and demonstrated its transcriptional activity by transfection experiments with the CAT gene as a reporter. We have also shown that this is a target gene for the action of PPARs, and we have localized a PPAR responsive element upstream of the first exon. These results show that PPAR regulates the entry of fatty acids into the mitochondria, which is a crucial step in their metabolism, especially in tissues like heart, skeletal muscle and brown adipose tissue in which fatty acids are a major source of energy.The incorporation of activated long-chain fatty acids into the mitochondria to be catabolized through -oxidation is produced by the mitochondrial carnitine palmitoyltransferase (CPT) 1 enzyme system. CPT I, the outer membrane component of this system, is the main control point in the -oxidation pathway. CPT I is thus a suitable site for pharmacological control of fatty acid oxidation in conditions such as diabetes or heart diseases.Two isoforms of CPT I have been described, which have been designated LCPT I and MCPT I since these isoforms are mainly expressed in liver and muscle respectively. The MCPT I gene is expressed not only in skeletal muscle but also in heart and brown and white adipose tissue (1-4). This expression pattern may be of great significance since fatty acids are a major source of energy for heart, skeletal muscle, and brown adipose tissue.The CPT I gene expression is regulated by fatty acids and peroxisome proliferators (5, 6). To gain more insight into the control of CPT I gene expression by fatty acids, we have examined the transcriptional regulation of CPT I genes. The expression of several genes involved in intra-and extracellular lipid metabolism, notably those involved in peroxisomal and mitochondrial -oxidation, is mediated by ligand-activated receptors collectively referred to as peroxisome proliferator-activated receptors (PPARs); these receptors are members of the nuclear receptor superfamily. PPARs are activated by a wide array of peroxisome proliferators and also by natural and synthetic fatty acids (7,8), antidiabetic drugs (9, 10), prostaglandin J 2 (10), and leukotriene B 4 (11).We have amplified by polymerase chain reaction (PCR) the 5Ј region of the human heart and brown adipose tissue CPT I gene and demonstrate, first, the transcriptional activity of this fragment and, second, the presence of a PPRE in the 5Ј-flanking region of this gene. In CV1 cells, the activation of the CPT I gene by PPAR was dependent on the ad...
Purpose: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma.The natural polyphenol (-)-epigallocatechin-3-gallate blocks in vitro FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and in vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models. Experimental Design: We evaluated the in vitro effects of the compounds on breast cancer cell growth (SK-Br3, MCF-7, and MDA-MB-231), apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase], cell signaling (HER2, ERK1/2, and AKT), and fatty acid metabolism enzymes (FASN and CPT-1). In vivo, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells. Results: Two compounds potently inhibited FASN activity and showed high cytotoxicity. Moreover, the compounds induced apoptosis and caused a marked decrease in the active forms of HER2, AKT, and ERK1/2 proteins. Interestingly, the compounds did not stimulate CPT-1 activity in vitro. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss in vivo. Fatty acid synthase (E.C.2.3.1.85; FASN) is a lipogenic enzyme which catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and NADPH precursors (1). FASN expression is generally low or undetectable in human tissues other than the liver and adipose tissue, and nonmalignant cells preferentially use circulating dietary fatty acids for the synthesis of new structural lipids. In contrast, high levels of FASN expression have been observed in breast cancer (2) and other human carcinomas (reviewed in ref.3). Importantly, several reports have shown that FASN expression levels correlate with tumor progression, aggressiveness, and metastasis, and are found elevated in the serum of patients with cancer
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