The stearoyl-CoA desaturase 1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids. This enzyme is a critical control point regulating hepatic lipogenesis and lipid oxidation. Therefore SCD1 may be a potential therapeutic target in the treatment of obesity and metabolic syndrome. Regulation of SCD1 expression occurs primarily at the level of transcription. In the present study, we characterized the insulin response elements (IREs) and the insulin signaling pathway mediating the regulation of SCD1 gene transcription in liver. In chicken embryo hepatocytes (CEH) and HepG2 cells, insulin stimulates SCD1 promoter activity by 2.5 folds. This activation is mediated by two different IREs on the chicken promoter, one localized between −1,975 and −1,610 bp and one between −372 and −297 bp. The latter binds both NF-Y and SREBP-1 transcription factors in response to insulin. We also demonstrated that insulin induction of SCD1 gene expression and promoter activity is abolished by pre-incubation of cells with specific inhibitors of both PI3-kinase (LY294002) and mTor (Rapamycin) or by over-expression of a dominant negative mutant of PI3-kinase. The PI3-kinase and mTor pathway mediates the insulin response on both IREs. In summary, insulin activates SCD1 gene expression in liver via a signaling pathway that involves PI3-kinase and mTor and the downstream transcription factors NF-Y and SREBP-1.Sentence summary: Insulin regulates SCD1 gene expression via two different IREs. The most 3′ IRE is localized between −372 and −297 bp and binds the NF-Y and SREBP-1 transcription factors in response to insulin. PI3-kinase and mTor mediate the action of insulin on both IREs.

is a key enzyme of hepatic lipogenesis responsible for the synthesis of long-chain saturated fatty acids. This enzyme is mainly regulated at the transcriptional level by nutrients and hormones. In particular, glucose, insulin, and T 3 increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T 3 and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T 3 response element (TRE) that mediates the T3 genomic effect, on the FAS promoter between Ϫ741 and Ϫ696 bp that mediates the T 3 genomic effect. We show that both T3 and insulin regulate FAS transcription via this sequence. The TRE binds a TR/RXR heterodimer even in the absence of hormone, and this binding is increased in response to T 3 and/or insulin treatment. The use of H7, a serine/threonine kinase inhibitor, reveals that a phosphorylation mechanism is implicated in the transcriptional regulation of FAS in response to both hormones. Specifically, we show that T 3 is able to modulate FAS transcription via a nongenomic action targeting the TRE through the activation of a PI 3-kinase-ERK1/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERK1/2 MAPK and PI 3-kinase/Akt. Finally, our data suggest that the nongenomic actions of T 3 and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence. fatty acid synthase; triiodothyronine; insulin; triiodothyronine response element; phosphoinositide 3-kinase; extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase LIPOGENESIS CONVERTS DIETARY CARBOHYDRATES to fatty acids primarily in liver (28). Insulin and triiodothyronine (T 3 ) are involved in mediating the effects of diet on lipogenesis in vivo (34). Hepatic lipogenesis is increased in hyperthyroid states or in response to T 3 injection (10,15,19,24,25,28,62,71,76,83) as well as in hyperinsulinemic subjects (80). In vivo, these two hormones are also involved in the long-term regulation of lipogenic enzymes activities such as fatty acid synthase (37).Fatty acid synthase (FAS; EC.2.3.1.85) is a key enzyme in hepatic lipogenesis. In the presence of NADPH, this multifunctional enzyme catalyzes the conversion of acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids such as palmitate and stearate (92). The de novo synthesis of fatty acids in human and chicken takes place mainly in the liver (30, 58), whereas in rodents the adipose tissue is also lipogenic (30). In vertebrates, FAS is a homodimer made of two identical peptide chains of ϳ260 kDa (85, 91), located in the cytoplasm of the cell (31). FAS is encoded by a unique gene that generates only one mRNA in mouse (73) and two in chicken and rat, as a result of alternative splicing (3). In the liver, the activity of FAS, like most lipogenic enzymes (95), is regulated through nutrients and hormones. Starvation causes a decrea...

BackgroundSurvival is poorer in elderly patients with head and neck squamous cell carcinomas [HNSCCs] than in younger patients. Possible explanations include a contribution of co-morbidities to mortality, frequent refusal of standard therapy, and the use of suboptimal treatments due to concern about toxicities. The Comprehensive Geriatric Assessment [CGA] is a multidimensional assessment of general health that can help to customise treatment and follow-up plans. The CGA has been proven effective in several health settings but has not been evaluated in randomised studies of patients with cancer. Our aim here was to assess the impact of the CGA on overall survival, function, and nutritional status of elderly patients with HNSCC.Methods/designEGeSOR is an open-label, multicentre, randomised, controlled, parallel-group trial in patients aged 70 years or older and receiving standard care for HNSCC. The intervention includes four components: the CGA conducted by a geriatrician before cancer treatment, participation of the same geriatrician in cancer treatment selection, a standardised geriatric therapeutic intervention designed by the same geriatrician; and geriatric follow-up for 24 months. The primary endpoint, assessed after 6 months, is a composite criterion including death, functional impairment [Activities of Daily Living score decrease ≥2], and weight loss ≥10%. Secondary endpoints include progression-free survival, unscheduled admissions, quality of life, treatment toxicities, costs, and completion of the planned cancer treatment. A centralised online system is used to perform 1:1 randomisation with a minimisation algorithm for centre, age, T and N stages, and tumour site [oral, oropharyngeal, hypopharyngeal, or laryngeal]. The estimated sample size is 704 patients, who are being recruited by 14 centres in 9 French cities.DiscussionEGeSOR is the first randomised trial of the CGA in elderly cancer patients. We expect the CGA to have direct clinical benefits on the management of elderly patients with HNSCC. If this expectation is fulfilled, the trial may lead to modifications of the management model for elderly patients with cancer.Trial registrationTrial registration: NCT02025062