The Roles of mTOR Complexes in Lipid Metabolism

Caron, Alexandre; Richard, Denis; Laplante, Mathieu

doi:10.1146/annurev-nutr-071714-034355

Cited by 267 publications

(213 citation statements)

References 156 publications

(198 reference statements)

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“…mTOR pathway, was also assessed, but again, no statistical difference was detected between groups. GLUT1, which increases glucose uptake into cells (28), was shown to be upregulated in the experimental group. Changes in protein fold were quantified and revealed that the greatest difference between the groups was in mTOR, p-mTOR, p4EBP1, pS6 and GLUT1 levels, all of which were increased in the knockout mice.…”

Section: Downstream Targets Of Mtor Were Upregulated Inmentioning

confidence: 88%

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Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

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Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-genespecific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6b H620Q/H620Q preclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing

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Section: Downstream Targets Of Mtor Were Upregulated Inmentioning

confidence: 88%

“…While the former two effectors -pS6 and p4EBP1 -stimulate protein synthesis, the lattermost -GLUT1 -regulates glucose transport (28). Specifically, GLUT1 increases glucose uptake into cells, and its upregulation may be indicative of increased metabolism.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

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“…To prevent the other nutrient intake changes (except dietary carbohydrate or protein intake), we employed a controlled-feeding method for in vivo studies. As our recent work demonstrated that hepatic lipogenesis requires the activation of mechanistic target of rapamycin complex 1 (mTORC1) in rainbow trout (14,15,42) as in mammals (9,41,63), and elevated amino acid levels enhanced hepatic fatty acid biosynthetic gene expression through an mTORC1-dependent manner (15), we also investigated the potential involvement of mTORC1 signaling pathway in the present study. Acute administration of rapamycin, a pharmacological inhibitor of mTOR, was employed to achieve an inhibition of mTORC1 and its downstream effectors, including p70 ribosomal S6 kinase 1 (S6K1), S6, and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) (14 -16, 42, 74).…”

mentioning

confidence: 99%

Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations

Dai

Panserat

Kaushik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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(DNL) remains debatable in carnivorous fish. We aimed to evaluate and compare the response of hepatic lipogenic gene expression to dietary carbohydrate intake/glucose and dietary protein intake/amino acids (AAs) during acute stimulations using both in vivo and in vitro approaches. For the in vivo trial, three different diets and a controlledfeeding method were employed to supply fixed amount of dietary protein or carbohydrate in a single meal; for the in vitro trial, primary hepatocytes were stimulated with a low or high level of glucose (3 mM or 20 mM) and a low or high level of AAs (one-fold or four-fold concentrated AAs). In vitro data showed that a high level of AAs upregulated the expression of enzymes involved in DNL [fatty acid synthase (FAS) and ATP citrate lyase (ACLY)], lipid bioconversion [elongation of very long chain fatty acids like-5 (Elovl5), Elovl2, ⌬6 fatty acyl desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD1)], NADPH production [glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme (ME)], and transcriptional factor sterol regulatory element binding protein 1-like, while a high level of glucose only elevated the expression of ME. Data in trout liver also showed that high dietary protein intake induced higher lipogenic gene expression (FAS, ACLY, and Elovl2) regardless of dietary carbohydrate intake, while high carbohydrate intake markedly suppressed the expression of acetyl-CoA carboxylase (ACC) and Elovl5. Overall, we conclude that, unlike rodents or humans, hepatic fatty acid biosynthetic gene expression in rainbow trout is more responsive to dietary protein intake/AAs than dietary carbohydrate intake/glucose during acute stimulations. This discrepancy probably represents one important physiological and metabolic difference between carnivores and omnivores. target of rapamycin; fatty acid biosynthesis; lipogenesis; protein; carbohydrate; rainbow trout DE NOVO LIPOGENESIS (DNL) is the metabolic pathway that synthesizes fatty acids from excess carbon donors; these fatty acids can then be converted into triglycerides, the major energy storage form in vertebrates (43,83,85). In mammals, hepatic lipogenesis is very responsive to dietary modifications (40). Consumption of a diet rich in carbohydrates stimulates the lipogenic pathway, whereas consumption of a diet rich in lipids and poor in carbohydrates, or rich in polyunsaturated fatty acids decreases this metabolic pathway (40,86). A highcarbohydrate diet can induce hyperglycemia, thereby stimulating lipogenesis via several mechanisms (40). First, by being glycolytically converted to acetyl-CoA, glucose provides substrate for fatty acid synthesis. Secondly, glucose stimulates glycolytic and lipogenic gene expression (24). Finally, glucose stimulates the release of insulin from the pancreas, thereby activating insulin/Akt signaling pathway (40, 69), which stimulates hepatic lipogenesis via the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) (32). Regarding dietary protein, rodent data showed that the meta...

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“…Activated mTOR stimulates angiogenesis, which increases the number of blood vessels through which nutrients can reach the cell. It also increases the production of nutrient transporter proteins that enhance the cell’s ability to import essential nutrients, and stimulates glycolysis and lipid metabolism [130]. Once extracellular and intracellular factors activate mTOR, it induces lipid and nucleotide synthesis and, in turn, promotes cell proliferation and survival.…”

Section: Local Molecular Mechanisms In Malnutrition and Cu Growthmentioning

confidence: 99%

Effect of Nutrition on Statural Growth

Gat-Yablonski

Luca

2017

Horm Res Paediatr

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In children, proper growth and development are often regarded as a surrogate marker for good health. A complex system controls the initiation, rate, and cessation of growth, and thus gives a wonderful example of the interactions between genetics, epigenetics, and environmental factors (especially stress and nutrition). Malnutrition is considered a leading cause of growth attenuation in children. This review summarizes our current knowledge regarding the mechanisms linking nutrition and skeletal growth, including systemic factors, such as insulin, growth hormone, insulin-like growth factor-1, fibroblast growth factor-21, etc., and local mechanisms, including mTOR, miRNAs, and epigenetics. Studying the molecular mechanisms regulating skeletal growth may lead to the establishment of better nutritional and therapeutic regimens for more effective linear growth in children with malnutrition and growth abnormalities.

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The Roles of mTOR Complexes in Lipid Metabolism

Cited by 267 publications

References 156 publications

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Hepatic fatty acid biosynthesis is more responsive to protein than carbohydrate in rainbow trout during acute stimulations

Effect of Nutrition on Statural Growth

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