RKIP phosphorylation–dependent ERK1 activation stimulates adipogenic lipid accumulation in 3T3-L1 preadipocytes overexpressing LC3

Hahm, Jong Ryeal; Ahmed, Mahmoud; Kim, Deok Ryong

doi:10.1016/j.bbrc.2016.07.107

Cited by 10 publications

(6 citation statements)

References 34 publications

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“…Insulin stimulates lipogenesis in several cell types and tissues in vitro and in vivo, − and lipogenesis occurs in parallel with the activation of lipogenesis-related transcription factors in response to insulin. , In our study, the intracellular and extracellular levels of TAG, PA, and SA were decreased as a result of serum starvation, increased following treatment with insulin, which was accompanied by fluctuations in mTORC1 activation and PPARγ and lipogenic gene expression in pBMECs. In our previous study, docosahexaenoic acid (DHA) secretion was inhibited by rapamycin in pBMECs, and another group found that mTOR signaling pathway and PPARγ are involved in stearic acid-induced triglyceride secretion by dairy cow mammary epithelial cells .…”

Section: Discussionsupporting

confidence: 51%

The mTORC1/4EBP1/PPARγ Axis Mediates Insulin-Induced Lipogenesis by Regulating Lipogenic Gene Expression in Bovine Mammary Epithelial Cells

Guo

Cheng

Feng

et al. 2019

J. Agric. Food Chem.

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4EBP1 is a chief downstream factor of mTORC1, and PPARγ is a key lipogenesis-related transcription factor. mTORC1 and PPARγ are associated with lipid metabolism. However, it is unknown which effector protein connects mTORC1 and PPARγ. This study investigated the interaction between 4EBP1 with PPARγ as part of the underlying mechanism by which insulin-induced lipid synthesis and secretion are regulated by mTORC1 in primary bovine mammary epithelial cells (pBMECs). Rapamycin, a specific inhibitor of mTORC1, downregulated 4EBP1 phosphorylation and the expression of PPARγ and the following lipogenic genes: lipin 1, DGAT1, ACC, and FAS. Rapamycin also decreased the levels of intracellular triacylglycerol (TAG); 10 types of fatty acid; and the accumulation of TAG, palmitic acid (PA), and stearic acid (SA) in the cell culture medium. Inactivation of mTORC1 by shRaptor or shRheb attenuated the synthesis and secretion of TAG and PA. In contrast, activation of mTORC1 by Rheb overexpression promoted 4EBP1 phosphorylation and PPARγ expression and upregulated the mRNA and protein levels of lipin 1, DGAT1, ACC, and FAS, whereas the levels of intracellular and extracellular TAG, PA, and SA also rose. Further, 4EBP1 interacted directly with PPARγ. Inactivation of mTORC1 by shRaptor prevented the nuclear location of PPARγ. These results demonstrate that mTORC1 regulates lipid synthesis and secretion by inducing the expression of lipin 1, DGAT1, ACC, and FAS, which is likely mediated by the 4EBP1/PPARγ axis. This finding constitutes a novel mechanism by which lipid synthesis and secretion are regulated in pBMECs.

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Section: Discussionsupporting

confidence: 51%

The mTORC1/4EBP1/PPARγ Axis Mediates Insulin-Induced Lipogenesis by Regulating Lipogenic Gene Expression in Bovine Mammary Epithelial Cells

Guo

Cheng

Feng

et al. 2019

J. Agric. Food Chem.

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“…Lipid droplet production and adipogenic transcription factor expression increase following overexpression of LC3 in 3T3-L1 preadipocytes. 174 Interestingly, p-(S153)-RKIP increases in a fashion parallel to ERK1 activation with adipogenic progression. Suppression of RKIP inhibitory activity also corresponds to intracellular accumulation of triacylglycerides in dexamethasone, 1-methyl-3-isobutylxanthine, and insulin (MDI-) induced mitotic expansion of growth-arrested preadipocytes.…”

Section: Rkip-lc3 Crosstalkmentioning

confidence: 97%

“…37,170–172 To date, only three studies have been published on the role of RKIP in autophagy and vice versa, or the closely related process of adipogenesis; only one of those three studies established a direct link between RKIP and LC3. 38,173,174…”

Section: Rkip-lc3 Crosstalkmentioning

confidence: 99%

A New Linkage between the Tumor Suppressor RKIP and Autophagy: Targeted Therapeutics

Wang

Bonavida

2018

Crit Rev Oncog

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The complexities of molecular signaling in cancer cells have been hypothesized to mediate cross-network alterations of oncogenic processes such as uncontrolled cell growth, proliferation, acquisition of epithelial-to-mesenchymal transition (EMT) markers, and resistance to cytotoxic therapies. The two biochemically exclusive processes/proteins examined in the present review are the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP) and the cell-intrinsic system of macroautophagy (hereafter referred to as autophagy). RKIP is poorly expressed in human cancer tissues, and low expression levels are correlated with high incidence of tumor growth, metastasis, poor treatment efficacy, and poor prognoses in cancer patients. By comparison, autophagy is a conserved cytoprotective degradation pathway that has been shown to influence the acquisition of resistance to hypoxia and nutrient depletion as well as the regulation of chemoimmuno-resistance and apoptotic evasion. Evidently, a broad library of cancer-relevant studies exists for RKIP and autophagy, although reports of the interactions between pathways involving RKIP and autophagy have been relatively sparse. To circumvent this limitation, the coordinate regulatory and effector mechanisms were examined for both RKIP and autophagy. Here, we propose three putative pathways that demonstrate the inherent pleiotropism and relevance of RKIP and the microtubule-associated protein 1 light chain 3 (MAP1LC3, LC3) on cell growth, proliferation, senescence, and EMT, among the hallmarks of cancer. Our findings suggest that signaling modules involving p53, signal transducer and activator of transcription 3 (STAT3), nuclear factor-κB (NF-κB), and Snail highlight the novel roles for RKIP in the control of autophagy and vice versa. The suggested potential crosstalk mechanisms are new areas of research in which to further study RKIP and autophagy in cancer models. These should lead to novel prognostic motifs and will provide alternative therapeutic strategies for the treatment of unresponsive aggressive cancer types.

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“…In 3T3-L1 cells, autophagy was inhibited by aspartate ammonia or 3-methyladenine at different lipid induction periods (0–2, 2–4, 4–6, and 6–8 days), and only autophagy inhibition at 0–2 days hindered the formation of lipid droplets and the expression of lipid marker genes, indicating that autophagy was very important in the early stage of lipid differentiation [ 120 ]. Recent studies showed that LC3 is overexpressed in 3T3-L1 cells, further demonstrating the important role of autophagy in lipid differentiation [ 121 ].…”

Section: Other Biochemical Response Involved In Adipocyte Differenmentioning

confidence: 99%

Molecular Mechanism of Stem Cell Differentiation into Adipocytes and Adipocyte Differentiation of Malignant Tumor

Zhang

Yang²,

Zhao

et al. 2020

Stem Cells International

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Adipogenesis is the process through which preadipocytes differentiate into adipocytes. During this process, the preadipocytes cease to proliferate, begin to accumulate lipid droplets, and develop morphologic and biochemical characteristics of mature adipocytes. Mesenchymal stem cells (MSCs) are a type of adult stem cells known for their high plasticity and capacity to generate mesodermal and nonmesodermal tissues. Many mature cell types can be generated from MSCs, including adipocyte, osteocyte, and chondrocyte. The differentiation of stem cells into multiple mature phenotypes is at the basis for tissue regeneration and repair. Cancer stem cells (CSCs) play a very important role in tumor development and have the potential to differentiate into multiple cell lineages. Accumulating evidence has shown that cancer cells can be induced to differentiate into various benign cells, such as adipocytes, fibrocytes, osteoblast, by a variety of small molecular compounds, which may provide new strategies for cancer treatment. Recent studies have reported that tumor cells undergoing epithelial-to-mesenchymal transition can be induced to differentiate into adipocytes. In this review, molecular mechanisms, signal pathways, and the roles of various biological processes in adipose differentiation are summarized. Understanding the molecular mechanism of adipogenesis and adipose differentiation of cancer cells may contribute to cancer treatments that involve inducing differentiation into benign cells.

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RKIP phosphorylation–dependent ERK1 activation stimulates adipogenic lipid accumulation in 3T3-L1 preadipocytes overexpressing LC3

Cited by 10 publications

References 34 publications

The mTORC1/4EBP1/PPARγ Axis Mediates Insulin-Induced Lipogenesis by Regulating Lipogenic Gene Expression in Bovine Mammary Epithelial Cells

The mTORC1/4EBP1/PPARγ Axis Mediates Insulin-Induced Lipogenesis by Regulating Lipogenic Gene Expression in Bovine Mammary Epithelial Cells

A New Linkage between the Tumor Suppressor RKIP and Autophagy: Targeted Therapeutics

Molecular Mechanism of Stem Cell Differentiation into Adipocytes and Adipocyte Differentiation of Malignant Tumor

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