Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes

Masuda, Masashi; Yoshida-Shimizu, Risa; Mori, Yukari; Ohnishi, Kohta; Adachi, Yuichiro; Sakai, Maiko; Kabutoya, Serina; Ohminami, Hirokazu; Yamanaka-Okumura, Hisami; Yamamoto, Hironori; Miyazaki, Masaru; Taketani, Yutaka

doi:10.1016/j.jnutbio.2022.109017

Cited by 24 publications

(15 citation statements)

References 56 publications

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“…In mature adipocytes, SIRT3 activated autophagy on lipid droplets (LDs) through activating ULK1, leading to smaller LDs and decreased lipid accumulation [ 50 ]. Sulforaphane was recently reported to induced lipophagy and decreased the size of LDs in differentiated 3T3-L1 adipocytes through activation of AMPK-mTOR-ULK1 pathway [ 51 ]. Whether ULK2 has multiple functions in adipocyte should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and post-transcriptional control of autophagy and adipogenesis by YBX1

Feng

et al. 2023

Cell Death Dis

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Obesity is strongly associated with metabolic diseases, which have become a global health problem. Exploring the underlying mechanism of adipogenesis is crucial for the treatment of excess white fat. Oncogene YBX1 is a multifunctional DNA- and RNA-binding protein that regulates brown adipogenesis. However, the role of YBX1 in white adipogenesis and adipose tissue expansion remains unknown. Here, we showed that YBX1 deficiency inhibited murine and porcine adipocyte differentiation. YBX1 positively regulated adipogenesis through promoting ULK1- and ULK2-mediated autophagy. Mechanistically, we identified YBX1 serves as a 5-methylcytosine (m5C)-binding protein directly targeting m5C-containing Ulk1 mRNA by using RNA immunoprecipitation. RNA decay assay further proved that YBX1 upregulated ULK1 expression though stabilizing its mRNA. Meanwhile, YBX1 promoted Ulk2 transcription and expression as a transcription factor, thereby enhancing autophagy and adipogenesis. Importantly, YBX1 overexpression in white fat enhanced ULK1/ULK2-mediated autophagy and promoted adipose tissue expansion in mice. Collectively, these findings unveil the post-transcriptional and transcriptional mechanism and functional importance of YBX1 in autophagy and adipogenesis regulation, providing an attractive molecular target for therapies of obesity and metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

Transcriptional and post-transcriptional control of autophagy and adipogenesis by YBX1

Feng

et al. 2023

Cell Death Dis

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“…Similarly, SFN was reported to induce lipophagy in adipocytes with increases of LC3, ATG5, and ULK1 protein expression. 27 Nrf2, publicly recognized as the target gene of SFN, has been found involved in macroautophagy regulation. 28,29 Consistent with previously published paper, 6 nrf 2 silence lowered the key macroautophagy protein expression including ATG7 and ATG5 and then SFN failed to regulate both these proteins (Figure 4B).…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane Ameliorates Hepatic Lipid Metabolism via Modulating Lipophagy In Vivo and In Vitro

Lei

Gao

et al. 2022

J. Agric. Food Chem.

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Although sulforaphane (SFN) is reported to ameliorate the excessive accumulation of lipid droplets (LDs) in hepatocytes, its underlying mechanism remains unclear. This paper aims to investigate how SFN induces hepatic LD degradation via activating macroautophagy. High-fat diet and free fatty acids (FFAs) were used to induce excessive LD formation in hepatocytes in vivo and in vitro, respectively. SFN-induced macroautophagy was shown by the increased LC3 protein expression both (1.32 ± 0.18) in vivo and (2.43 ± 0.22) in vitro. The mRNA levels of Lc3 (1.99 ± 0.16), Atg4 (2.12 ± 0.23), Ulk1 (1.19 ± 0.12), Atg7 (1.25 ± 0.11), and Atg5 (0.81 ± 0.1) genes were elevated by SFN. SFN individually enhanced the localization of LC3 (0.41 ± 0.15), LAMP1 (0.66 ± 0.14), ATG7 (0.26 ± 0.08), and ATG5 (0.38 ± 0.09) with LDs, indicating the occurrence of lipophagy. In the components of LDs isolated from SFN treatment, the expressions of LC3, ATG7, and ATG5 protein were largely increased both in vivo and in vitro. LDs were visualized in autophagosomes which confirmed that the lipophagy was triggered by SFN. Moreover, SFN treatment improved the profile of FFAs which was characterized by increasing the FFAs in liver (total FFA: 261.51 ± 39.58 μM/g) and serum (total FFA: 967.59 ± 239.18 nM/mL). After silencing the nrf 2 gene, ATG7 and ATG5 protein expressions were decreased and attenuated this induction by SFN. Nrf2 gene silencing inversely increased TG contents. In summary, SFN enhanced the LD degradation via stimulating lipophagy in a Nrf2-dependent manner.

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“…For example, the glucagon-like peptide 1 (GLP-1) analog liraglutide (LRG) restores lipophagy by increasing AMPK activity, ultimately improving hepatocyte steatosis ( He et al, 2016 ). Chemotherapeutic isothiocyanate radixanthin (SFN) contributes to lipophagy in adipocytes of mice fed HFD and induces lipophagy via the AMPK-mTOR-ULK1 signaling pathway in differentiated 3T3-L1 cells ( Masuda et al, 2022 ).…”

Section: Targeting Mtorc1-dependent Lipophagy For the Treatment Of Nafldmentioning

confidence: 99%

The essential effect of mTORC1-dependent lipophagy in non-alcoholic fatty liver disease

Tan

Huang²,

Lu³

et al. 2023

Front. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease with increasing prevalence. Lipophagy is a type of programmed cell death that plays an essential role in maintaining the body’s balance of fatty acid metabolism. However, the livers of NAFLD patients are abnormally dysregulated in lipophagy. mTORC1 is a critical negative regulator of lipophagy, which has been confirmed to participate in the process of lipophagy through various complex mechanisms. Therefore, targeting mTORC1 to restore failed autophagy may be an effective therapeutic strategy for NAFLD. This article reviews the main pathways through which mTORC1 participates in the formation of lipophagy and the intervention effect of mTORC1-regulated lipophagy in NAFLD, providing new therapeutic strategies for the prevention and treatment of NAFLD in the future.

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Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes

Cited by 24 publications

References 56 publications

Transcriptional and post-transcriptional control of autophagy and adipogenesis by YBX1

Transcriptional and post-transcriptional control of autophagy and adipogenesis by YBX1

Sulforaphane Ameliorates Hepatic Lipid Metabolism via Modulating Lipophagy In Vivo and In Vitro

The essential effect of mTORC1-dependent lipophagy in non-alcoholic fatty liver disease

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