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The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ ; 16 — Download references. We would like to thank our colleague Mr Steve Plouffe for critical reading of this manuscript.

This work was supported by National Institutes of Health NIH grants to KLG. RCR is supported by a Canadian Institutes of Health Research CIHR postdoctoral fellowship.

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, , CA, USA. You can also search for this author in PubMed Google Scholar. Correspondence to Kun-Liang Guan. Reprints and permissions. Russell, R. Autophagy regulation by nutrient signaling. Cell Res 24 , 42—57 Download citation.

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Download PDF. Subjects Autophagy Nutrient signalling. Abstract The ability of cells to respond to changes in nutrient availability is essential for the maintenance of metabolic homeostasis and viability.

Gαq activation modulates autophagy by promoting mTORC1 signaling Article Open access 27 July How does mTOR sense glucose starvation? AMPK is the usual suspect Article Open access 22 April Introduction Macroautophagy, referred to hereafter simply as autophagy, is the primary catabolic program activated by cellular stressors including nutrient and energy starvation 1.

The core autophagy proteins In order to explain autophagy regulation, we will first describe the autophagy machinery in this section. Autophagy initiation In mammals, the site of origin for autophagosome formation is the phagophore.

ATG protein recruitment to the phagophore initiates autophagy One of the earliest detectable events in autophagy initiation is the formation of ULK1 puntca 30 Figure 1.

Figure 1. Full size image. Amino acid signaling to mTORC1 The knowledge that autophagy is responsive to fluctuations in amino acids predates the identification and cloning of the ATG genes. Figure 2. Downstream targets of mTORC1 in autophagy mTORC1 is established as a potent repressor of autophagy in eukaryotes TORC1 in yeast.

Figure 3. Box1 mTOR signaling and autophagy in MLIV MLIV is caused by a deficiency in the cation channel encoded by MCOLN1. Energetic stress and AMPK signaling In order to maintain metabolic homeostasis, the cell must strictly match the generation and consumption of ATP. Downstream targets of AMPK in autophagy Activation of autophagy in response to energetic stress is an essential mechanism to maintain metabolic homeostasis and cell viability.

Table 1 Beclin-1 interacting proteins implicated in starvation-induced autophagy Full size table. Oxygen availability Oxygen is an essential nutrient that is required for key metabolic processes within the cell. The autophagy initiating kinase ULK ULK is the most upstream ATG protein regulating autophagy initiation in response to inductive signals.

Downstream targets of ULK Despite ULK's pivotal role in conveying nutrient signal to the autophagy cascade, the mechanisms and downstream targets responsible were until recently enigmatic.

ULK1 feedback loops ULK1 has recently been described to initiate two feedback loops. Regulation of VPSkinase complexes in response to nutrients Generation of PtdIns 3 P at the phagophore is necessary for the expansion of the membrane.

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Recent studies have reported that the regulation of autophagy has a beneficial role against these conditions. When there is plenty of food, nutrient-sensing pathways activate anabolism and storage, but the shortage of food activates homeostatic mechanisms like autophagy, which mobilises internal stockpiles.

These nutrient-sensing pathways are well conserved in eukaryotes and are involved in the regulation of autophagy which includes SIRT1, mTOR and AMPK.

The current review focuses on the role of SIRT1, mTOR and AMPK in regulating autophagy and suggests autophagy along with these nutrient-sensing pathways as potential therapeutic targets in reducing the progression of various diabetic complications. Keywords: AMPK; Diabetic cardiomyopathy; Diabetic nephropathy; Diabetic neuropathy; Diabetic retinopathy; MTOR; SIRT1.

Abstract The incidence of diabetes has been increasing in recent decades which is affecting the population of both, developed and developing countries. Publication types Review.

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Download references. We thank N. Yoshimori for the mRFP—GFP—LC3 plasmid; M. Townley and M. Mancini for transmission electron microscopy and confocal microscopy; the members of the Moore laboratory for comments and additional support.

Core facilities supported by grants U54 HD, P30 DXA2, P39 CA and S10RRA1. Next-generation sequencing was performed by the Functional Genomics Core of the Penn Diabetes Research Center DK This work was supported by funding from the Alkek Foundation and the Robert R.

Doherty Jr-Welch Chair in Science to D. Present address: Present addresses: Laboratory of Experimental Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A Graz, Austria M. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, , Texas, USA.

Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, , Pennsylvania, USA.

You can also search for this author in PubMed Google Scholar. conceived the project, designed and performed most experiments, interpreted results, and co-wrote the manuscript. performed animal experiments and participated in discussion of the results.

analysed PPARα and FXR ChIP-seq data, and designed primers for PPARα ChIP-qPCR. performed ChIP assays and molecular cloning. performed PPARα ChIP-seq. supervised experimental designs.

conceived the project, supervised experimental designs, interpreted results, and co-wrote the manuscript. Correspondence to David D.

a , Autophagic flux was assessed by LC3 immunoblot analysis in AML12 cells treated with indicated dose of Wy,, or co-treated with both Wy, and bafilomycin A 1 BafA1. GWtreated cells were starved for 2 h. GFP—LC3 cleavage was assessed by GFP immunoblot analysis.

e , LC3 immunoblot in AML12 cells treated with indicated doses of GW or co-treated with GW and Torin1. All drug treatments were done in complete media for 24 h unless otherwise indicated.

β-actin is a loading control. f , Quantification of autophagic flux shown in Fig. Data represent mean ± s. GWtreated cells were starved in HBSS medium for 1 h. c , Bile acids suppress autophagosome formation. AML12 cells were treated with indicated doses of each bile acid for 24 h, followed by 1-h starvation in HBSS medium.

e , f , Fed ad libitum , 24 h fasted, or 24 h refed after 24 h fasting wild-type mice were euthanized to collect livers at Proteins 50 μg from liver homogenates were separated by SDS—PAGE and probed with the indicated antibodies.

g , Hepatic expression levels of PPARα or FXR target gene Acox1 and Cyp7a1 , respectively were determined by qPCR analysis. a , c , Hepatic expression levels of autophagy-related genes LC3a , LC3b and Atg12 , PPARα-target gene Acox1 and FXR-target gene SHP were determined by qPCR analysis. Fed or fasted wild-type mice were orally gavaged with vehicle, GW or GW twice a day.

e , Representative confocal images out of nine tissue sections per condition of GFP—LC3 puncta green: autophagosomes and DAPI blue: DNA staining in livers. Liver samples were fixed and cryosections were analysed by confocal microscopy.

Scale bars, 50 μm. DNA was stained with DAPI blue. Scale bars, 20 μm. Quantification of lipophagic vacuoles shown in f and Fig. g , Measuring β-hydroxybutyrate. AML12 cells were transiently transfected with control siRNA siControl , Atg5 siRNA siAtg5 or Atg7 siRNA siAtg7 for 24 h followed by indicated drug treatments for 48 h with or without μM oleate vehicle: 0.

h , Serum β-hydroxybutyrate were normalized to liver weights. Data are mean ± s. Statistics by two-tailed t -test. Magnification of representative transmission electron micrograph images out of 30 cells per group of livers. Lipophagy yellow arrowheads , autophagosomes blue arrowheads , autolysosomes red arrowheads , microautophagy black arrowheads and multivesicular bodies purple arrowheads.

Scale bars, 0. Eleven genes in a were induced by PPARα activation, but not affected by FXR activation. Altered expression levels of 13 genes shown in Fig. a , De novo motif analysis of PPARα-bound genomic regions. Top PPARα peak regions ± base pairs bp from peak summits, ranked by enrichment fold were subjected to de novo motif discovery by MEME.

b , Venn diagram depicting increasing PPARα cistrome upon PPARα agonism in vivo. c , Venn diagram showing overlapping binding peaks between PPARα ChIP-seq and FXR ChIP-seq from wild-type mice treated with synthetic agonists GW or GW d , Autophagy-related genes of PPARα and FXR cistrome.

FXR ChIP-seq showed that 3, genes have peaks in wild-type mice treated with GW, and 61 out of autophagy-related genes have at least one FXR peak.

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