Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

Singh, Brijesh Kumar; Sinha, Rohit Anthony; Zhou, Jin; Tripathi, Madhulika; Ohba, Kenji; Wang, Mu-En; Astapova, Inna; Ghosh, Sujoy; Hollenberg, Anthony N.; Gauthier, Karine; Yen, Paul M.

doi:10.1074/jbc.m115.668673

Cited by 45 publications

(51 citation statements)

References 57 publications

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“…Although increased mitochondrial uncoupling by T 3 in BAT did not induce ROS and AMPK activity, it can increase NAD + /NADH ratio and activate SIRT1. We have previously shown that T 3 activates SIRT1 [50], a NAD + -dependent histone deacetylase that is a negative regulator of MTOR [34], in hepatocytes. Consistent with its ability to increase mitochondrial respiration and uncoupling, T 3 also increased intracellular NAD + /NADH and activated SIRT1 within 3 to 6 h in BAT and primary brown adipocytes as well as liver [50] (Figure 7(d)).…”

Section: T 3 Inhibits Mtor Activity By Amino Acid Catabolism and Sirtmentioning

confidence: 99%

“…We have previously shown that T 3 activates SIRT1 [50], a NAD + -dependent histone deacetylase that is a negative regulator of MTOR [34], in hepatocytes. Consistent with its ability to increase mitochondrial respiration and uncoupling, T 3 also increased intracellular NAD + /NADH and activated SIRT1 within 3 to 6 h in BAT and primary brown adipocytes as well as liver [50] (Figure 7(d)). Interestingly, T 3 was unable to decrease MTOR activity, induce autophagy, or increase oxidative phosphorylation when SIRT1 was inhibited (Figure 8(f,g,h)), suggesting that T 3 -mediated MTOR inhibition and autophagy in BAT required SIRT1.…”

Section: T 3 Inhibits Mtor Activity By Amino Acid Catabolism and Sirtmentioning

confidence: 99%

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Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

et al. 2018

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The thyroid hormone triiodothyronine (T) activates thermogenesis by uncoupling electron transport from ATP synthesis in brown adipose tissue (BAT) mitochondria. Although T can induce thermogenesis by sympathetic innervation, little is known about its cell autonomous effects on BAT mitochondria. We thus examined effects of T on mitochondrial activity, autophagy, and metabolism in primary brown adipocytes and BAT and found that T increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis. Interestingly, there was no significant induction of intracellular reactive oxygen species (ROS) despite high mitochondrial respiration and UCP1 induction by T. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T decreased, and was accompanied by ROS accumulation, demonstrating a critical role for autophagic mitochondrial turnover. We next generated an Atg5 conditional knockout mouse model (Atg5 cKO) by injecting Ucp1 promoter-driven Cre-expressing adenovirus into Atg5 mice to examine effects of BAT-specific autophagy on thermogenesis in vivo. Hyperthyroid Atg5 cKO mice exhibited lower body temperature than hyperthyroid or euthyroid control mice. Metabolomic analysis showed that T increased short and long chain acylcarnitines in BAT, consistent with increased β-oxidation. T also decreased amino acid levels, and in conjunction with SIRT1 activation, decreased MTOR activity to stimulate autophagy. In summary, T has direct effects on mitochondrial autophagy, activity, and turnover in BAT that are essential for thermogenesis. Stimulation of BAT activity by thyroid hormone or its analogs may represent a potential therapeutic strategy for obesity and metabolic diseases. Abbreviations: ACACA: acetyl-Coenzyme A carboxylase alpha; AMPK: AMP-activated protein kinase; Acsl1: acyl-CoA synthetase long-chain family member 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; BAT: brown adipose tissue; cKO: conditional knockout; COX4I1: cytochrome c oxidase subunit 4I1; Cpt1b: carnitine palmitoyltransferase 1b, muscle; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DIO2: deiodinase, iodothyronine, type 2; DMEM: Dulbecco's modified Eagle's medium; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; Fabp4: fatty acid binding protein 4, adipocyte; FBS: fetal bovine serum; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FGF: fibroblast growth factor; FOXO1: forkhead box O1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Gpx1: glutathione peroxidase 1; Lipe: lipase, hormone sensitive; MAP1LC3B: microtubule-associated protein 1 light chain 3; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; NAD: nicotinamide adenine dinucleotide; Nrf1: nuclear respiratory factor 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PPARGC1A: peroxisome proliferati...

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Section: T 3 Inhibits Mtor Activity By Amino Acid Catabolism and Sirtmentioning

confidence: 99%

Section: T 3 Inhibits Mtor Activity By Amino Acid Catabolism and Sirtmentioning

confidence: 99%

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

et al. 2018

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“…An aliquot was removed, and protein concentrations were measured using the BCA kit (Bio-Rad). Western blotting was performed using a standard protocol, as described previously [55]. Primary…”

Section: Protein Extraction and Expression Analysis By Western Blottingmentioning

confidence: 99%

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Singh

Tripathi

Yen

et al. 2020

Preprint

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Although in vitro senescence models have been developed using primary fibroblasts, they may not be applicable for the study of metabolically active organs such as the liver. We thus developed an in vitro protocol to induce senescence in AML12 nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Sequential oxidative stress with hydrogen peroxide induced premature senescence in these cells as they exhibited molecular and metabolic signatures, had increased SA-Gal and H2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled the livers from aged mice.Metabolic phenotyping showed fuel switching towards more glycolysis, mitochondrial glutamine oxidation, and impaired energy production that also was similar to the livers from aged mice. Additionally, Senescence Activated Secretory Proteins (SASPs) sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated an in vitro senescent AML12 cell model that not only show the molecular hallmarks of aging, but also recapitulates the aberrant metabolic phenotype found in aged liver. As such, they represent a novel and useful model to study nutritional, pharmacological, or genetic factors on hepatic metabolism during aging.

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“…2B-D) [16,17,[25][26][27]135]. These autophagy-related genes could be regulated directly by T 3 /THR at the transcriptional level or indirectly through FOXO1 activation by dephosphorylation and deacetylation via TH-activated SIRT1 [136,137]. SIRT1 is a NAD + -dependent deacetylase activated by increases in cellular NAD + levels that serves as an energy sensor of cells to control transcriptional activity by T 3 and FOXO1.…”

Section: Th/thr Regulation Of Hepatic Autophagymentioning

confidence: 99%

“…SIRT1 is a NAD + -dependent deacetylase activated by increases in cellular NAD + levels that serves as an energy sensor of cells to control transcriptional activity by T 3 and FOXO1. Furthermore, SIRT1 mediates T 3 -induced autophagy through stimulation of expression as well as deacetylation of autophagy-related genes [136]. The master transcription factor, transcription factor EB (TFEB), regulates autophagy and lysosome-related genes may additionally be modulated by TH [44].…”

Section: Th/thr Regulation Of Hepatic Autophagymentioning

confidence: 99%

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

Chi

Tsai

et al. 2019

J Biomed Sci

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The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer. Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues. Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed.

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Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

Cited by 45 publications

References 57 publications

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

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Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

Cited by 45 publications

References 57 publications

Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

Contact Info

Product

Resources

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Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy