Assessing the Activity of Transcription Factor FoxO1

Shi, Limin; Tao, Zhipeng; Cheng, Zhiyong

doi:10.1007/978-1-0716-2815-7_8

“…These substrates are involved in various cellular processes, such as glucose metabolism, lipid metabolism, oxidative stress, cell cycle arrest, and apoptosis. FOXO1 has been implicated (37)(38)(39)(40) in the pathogenesis and prevention of various diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, and cancers. For example, FOXO1 can improve insulin sensitivity and glucose homeostasis by regulating gluconeogenic enzymes, and GLUT4 expression can inhibit adipogenesis and lipogenesis by suppressing PPARγ and SREBP-1c expression.…”

Section: Resultsmentioning

confidence: 99%

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

Raghavan¹

2023

Preprint

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There are seven sirtuin genes in humans that encode seven sirtuin enzymes (SIRT1–7), each of which has unique functions and subcellular locations. Sirtuins are NAD+-dependent protein deacetylases that play a significant role in physiological processes such as energy metabolism, stress responses, DNA repair, and gene expression. Sirtuins are essential targets for aging-related diseases such as type 2 diabetes, inflammatory diseases, and neurodegenerative disorders. However, finding a single molecule that can activate all seven sirtuin genes is challenging because each isoform has a unique structure, substrates, and regulatory mechanisms. Most known sirtuin activators are specific for SIRT1, the most studied isoform of the sirtuin family. Here, we report that Metadichol®, a nano-emulsion of long-chain alcohols, induces 3- to 15-fold expression of all SIRT1–7 genes in human dermal fibroblasts when used in concentrations ranging from 1 pg/mL to 100 ng/mL. SIRT3 and FOXO1 gene expressions were 15-fold higher than those after treatment with Metadichol®. In addition, KL, FOXO1, TERT, and TP53 exhibited increased expression. Sirtuins and the four genes regulate aging, metabolism, and DNA repair and are age-related diseases like cancer, cardiovascular disease, and diabetes. All of these genes play essential roles in improving the quality of life as we age.

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“…These substrates are involved in various cellular processes, such as glucose metabolism, lipid metabolism, oxidative stress, cell cycle arrest, and apoptosis. FOXO1 has been implicated (37)(38)(39)(40) in the pathogenesis and prevention of various diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, and cancers. For example, FOXO1 can improve insulin sensitivity and glucose homeostasis by regulating gluconeogenic enzymes, and GLUT4 expression can inhibit adipogenesis and lipogenesis by suppressing PPARγ and SREBP-1c expression.…”

Section: Resultsmentioning

confidence: 99%

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

Raghavan¹

2023

Preprint

View full text Add to dashboard Cite

There are seven sirtuin genes in humans that encode seven sirtuin enzymes (SIRT1–7), each of which has unique functions and subcellular locations. Sirtuins are NAD+-dependent protein deacetylases that play a significant role in physiological processes such as energy metabolism, stress responses, DNA repair, and gene expression. Sirtuins are essential targets for aging-related diseases such as type 2 diabetes, inflammatory diseases, and neurodegenerative disorders. However, finding a single molecule that can activate all seven sirtuin genes is challenging because each isoform has a unique structure, substrates, and regulatory mechanisms. Most known sirtuin activators are specific for SIRT1, the most studied isoform of the sirtuin family. Here, we report that Metadichol®, a nano-emulsion of long-chain alcohols, induces 3- to 15-fold expression of all SIRT1–7 genes in human dermal fibroblasts when used in concentrations ranging from 1 pg/mL to 100 ng/mL. SIRT3 and FOXO1 gene expressions were 15-fold higher than those after treatment with Metadichol®. In addition, KL, FOXO1, TERT, and TP53 exhibited increased expression. Sirtuins and the four genes regulate aging, metabolism, and DNA repair and are age-related diseases like cancer, cardiovascular disease, and diabetes. All of these genes play essential roles in improving the quality of life as we age.

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“…3T3L1 cells (CL-173™, ATCC) were cultured and induced for differentiation as described previously [ 2 , 25 ]. When applicable, the preadipocytes and adipocytes were treated for 3–4 days with vehicle (DMSO), FoxO1 inhibitor AS1842856 (1 μM), autophagy inhibitor Bafilomycin A1 (0.1 μM), and siRNAs against Pgc1α, Fundc1, and Atg7 using Lipofectamine® RNAiMAX Reagent (cat # 13778150, ThermoFisher) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…The procedure was performed as described [ 2 , 25 ]. Specifically, tissue and cell lysates were prepared with PLC lysis buffer (30 mM Hepes, pH 7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl 2 , 1 mM EGTA, 10 mM NaPPi, 100 mM NaF, 1 mM Na 3 VO 4 ) supplemented with protease inhibitor cocktail (Roche) and 1 mM PMSF.…”

Section: Methodsmentioning

confidence: 99%

Loss of FoxO1 activates an alternate mechanism of mitochondrial quality control for healthy adipose browning

Shi,

Yang,

Tao

et al. 2024

Clinical Science

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Browning of white adipose tissue is hallmarked by increased mitochondrial density and metabolic improvements. However, it remains largely unknown how mitochondrial turnover and quality control are regulated during adipose browning. In the present study, we found that mice lacking adipocyte FoxO1, a transcription factor that regulates autophagy, adopted an alternate mechanism of mitophagy to maintain mitochondrial turnover and quality control during adipose browning. Post-developmental deletion of adipocyte FoxO1 (adO1KO) suppressed Bnip3 but activated Fundc1/Drp1/OPA1 cascade, concurrent with up-regulation of Atg7 and CTSL. In addition, mitochondrial biogenesis was stimulated via the Pgc1α/Tfam pathway in adO1KO mice. These changes were associated with enhanced mitochondrial homeostasis and metabolic health (e.g., improved glucose tolerance and insulin sensitivity). By contrast, silencing Fundc1 or Pgc1α reversed the changes induced by silencing FoxO1, which impaired mitochondrial quality control and function. Ablation of Atg7 suppressed mitochondrial turnover and function, causing metabolic disorder (e.g., impaired glucose tolerance and insulin sensitivity), regardless of elevated markers of adipose browning. Consistently, suppression of autophagy via CTSL by high-fat diet was associated with a reversal of adO1KO-induced benefits. Our data reveal a unique role of FoxO1 in coordinating mitophagy receptors (Bnip3 and Fundc1) for a fine-tuned mitochondrial turnover and quality control, underscoring autophagic clearance of mitochondria as a prerequisite for healthy browning of adipose tissue.

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Assessing the Activity of Transcription Factor FoxO1

Cited by 8 publications

References 19 publications

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

Loss of FoxO1 activates an alternate mechanism of mitochondrial quality control for healthy adipose browning

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