A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

Ito, Minoru; Nagasawa, Michiaki; Omae, Naoki; Tsunoda, Masaki; Ishiyama, Jun‐ichi; Ide, Tomohiro; Akasaka, Yunike; Murakami, Koji

doi:10.1194/jlr.m031591

Cited by 35 publications

(25 citation statements)

References 56 publications

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“…Our results are consistent with previous studies that describe a positive role of JNK in adipose lipogenesis (55)(56)(57). JNK1 depletion using anti-sense oligonucleotides in adipose tissue attenuates the expression of lipogenic enzymes Acly, Acaca, Fasn, and Scd-1 ( 55 ) and JNK2 suppression in human adipocytes attenuates Srebp-1 expression and activity resulting in decreased target lipid enzymes ( 57 ).…”

Section: Map4k4 Depletion Requires Srebp Expression To Enhance Lipid supporting

confidence: 82%

“…JNK1 depletion using anti-sense oligonucleotides in adipose tissue attenuates the expression of lipogenic enzymes Acly, Acaca, Fasn, and Scd-1 ( 55 ) and JNK2 suppression in human adipocytes attenuates Srebp-1 expression and activity resulting in decreased target lipid enzymes ( 57 ). Mice expressing a mature transcriptionally active Srebp-1 variant lacking all of the JNK phosphorylation sites are protected from hepatic steatosis and weight gain, thus demonstrating that JNK positively regulates Srebp-1 function lipogenesis.…”

Section: Map4k4 Depletion Requires Srebp Expression To Enhance Lipid mentioning

confidence: 99%

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Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling

Danai

Guilherme

Straubhaar

et al. 2013

Journal of Lipid Research

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Extreme human obesity triggers adipose dysfunction, paradoxically resulting in decreased capacity for lipid synthesis and contributing to ectopic lipid deposition, lipotoxicity, and whole-body insulin resistance ( 1 ). Lipo dy strophic human subjects and mouse models demonstrate that deficits in adipose lipogenesis correlate with excess lipid deposition in liver and muscle as well as whole-body insulin resistance, highlighting the importance of adipose lipogenesis in metabolic dysfunction ( 1-4 ). Adipose tissue expression and activity of the lipogenic transcription factors peroxisome proliferator-activated receptor ␥ ( PPAR ␥ ), sterol-regulated element binding protein-1 (Srebp-1), and carbohydrate-responsive element binding protein (Chrebp, also known as Mlxipl) are suppressed in obese humans, leading to decreased expression of lipogenic enzymes and decreased adipose fatty acid (FA) and triglyceride (TG) synthesis; however, the mechanisms that lead to this inhibition are unclear ( 2, 3, 5-10 ). Therefore, understanding this deregulation is fundamental in developing strategies that promote adipose lipogenesis, to increase lipid sequestration in adipocytes and prevent ectopic fat deposition during obesity.Srebp-1 and Srebp-2 are transcription factors important for regulating the expression of genes involved in synthesis and uptake of cholesterol, FAs, TGs, and phospholipids ( 11 ). These factors reside in the endoplasmic reticulum and upon demand for lipid synthesis are transported to the Golgi apparatus where they are cleaved, allowing the functional N-terminal fragment to translocate into the Abbreviations: Acaca, acetyl-CoA carboxylase ␣ ; Ad, adenovirus; Acly, ATP citrate lyase; AMPK, AMP-protein kinase; AP-1, activator protein-1; Chrebp, carbohydrate-responsive element binding protein; CMV, cytomegalovirus; JNK, c-Jun NH 2 -terminal kinase; HA, hemagglutinin; Map4k4, mitogen-activated protein kinase kinase kinase kinase 4; mTOR, mechanistic target of rapamycin; mTORC1; mechanistic target of rapamycin complex 1; MBP, myelin basic protein; PPAR ␥ , peroxisome proliferator-activated receptor ␥ ; RNAi, RNA interference; Scd-1, stearoyl-CoA desaturase 1; siRNA, small interfering RNA; TG, triglyceride; TNF ␣ , tumor necrosis factor ␣ ; Srebp-1, sterol-regulated element binding protein-1 .

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Section: Map4k4 Depletion Requires Srebp Expression To Enhance Lipid supporting

confidence: 82%

Section: Map4k4 Depletion Requires Srebp Expression To Enhance Lipid mentioning

confidence: 99%

Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling

Danai

Guilherme

Straubhaar

et al. 2013

Journal of Lipid Research

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“…MAP kinase-related signals has been implicated in the transcriptional activation of SREBPs [34]. Here we provide evidence of the role of JNK activation on SREBP-2 processing and LDLR expression.…”

Section: Discussionmentioning

confidence: 53%

“…JNK activation is better understood in the regulation of SREBP-1c-mediated gene expression. JNK2 increases insulin-mediated activation of SREBP-1c for de novo fatty acid synthesis [34]. Another MAPK, ERK, mediates the signals initiated by insulin and platelet-derived growth factor [36].…”

Section: Discussionmentioning

confidence: 99%

JNK-Mediated SREBP-2 Processing by Genistein up-regulates LDLR Expression in HepG2 Cells

Lee

Han²,

Kim³

2014

J Nutr Food Sci

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Genistein has been implicated for its anti-atherogenic effects. We investigated the molecular mechanisms behind the impact of genistein on expression of LDLR, the receptor for LDL-cholesterol, and related signaling pathways in HepG2 cells. Genistein increased mRNA and protein levels of LDLR in a time-dependent manner. In order to find out the effects of genistein on the transcriptional levels, a luciferase reporter construct containing LDLR promoter (pLDLR-luc) was constructed and examined for its response to genistein. Genistein increased the reporter activity but failed to increase transcriptional activity when sterol-regulatory element (SRE) in the LDLR promoter was deleted. Genistein increased nuclear translocation of SREBP-2 and DNA binding activity of SREBP-2 to LDLR promoter by chromatin immunoprecipitation assay (CHIP). Pre-treatment of 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), serine protease inhibitor, prevented the effects of genistein while brefeldin A causing the fusion of the endoplasmic reticulum (ER) and the Golgi apparatus did not, suggesting that genistein may have an effect on SREBP-2 trafficking from the ER to the Golgi apparatus. Insig-1 protein levels were not changed by genistein. Among mitogen-activated protein kinases (MAPK), genistein phosphorylated JNK but not p38 and ERK signals. JNK inhibitor (SP600126) abolished genistein-stimulated levels of LDLR and nuclear SREBP-2. To minimize the effects of c-Jun, a transcription factor activated by JNK signals, a truncated LDLR luciferase construct that contained SRE but lacked the c-jun putative binding site was constructed. Genistein still was able to boost the transcriptional activity of the truncated LDLR construct. All the genistein effects were abolished by the addition of cholesterol. In conclusion, genistein has the anti-atherogenic effects by activating JNK signals and SREBP-2 processing, which is followed by up-regulation of LDLR. However, the beneficial effects of genistein could be affected by the amount of cellular cholesterols.

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“…Increased JNK activity in adipose tissue has also been demonstrated. Literature data show that molecular targeting and selective inactivation of JNK1 and JNK2 in adipose tissue can protect against increased adiposity and insulin resistance induced by high fat diet Sirin and Kolonin, 2013;Ito et al, 2013). Recent evidence shows alterations in JNK signaling in prostate, breast, pancreas, lung cancer, mutations in JNK pathway were reported to be involved in cancer development too (Kan et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

JNK implication in adipocyte-like cell death induced by chemotherapeutic drug cisplatin

Krestnikova¹,

Stulpinas²,

Imbrasaitė³

et al. 2015

J. Toxicol. Sci.

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-Recent evidence shows that tumor microenvironment containing heterogeneous cells may be involved in cancer initiation, growth and tumor cell response to anticancer therapy. Chemotherapy was designed to make toxic impact on malicious cells in organisms, however, the means to protect healthy cells against chemical toxicity are still unsuccessful. As known, the majority of tumor surrounding cells are cancer-associated adipocytes which influence cancer development, progression and treatment. Targeting the components of tumor microenvironment in combination with conventional cancer treatment may become an effective cancer therapy strategy. However, little is known about adipocyte death mechanisms during combined chemo-and targeted therapy. The importance of c-Jun-NH 2 -terminal kinase (JNK) signaling in tumor development and treatment has been demonstrated using various in vitro and in vivo cancer models. The aim of this study was to ascertain adipocyte viability during simultaneous stress kinase JNK inhibition and exposure to one of the most commonly used anticancer drugs cis-diamminedichloroplatinum II (cisplatin). Our model involved adipocyte-like cells (ADC) which were obtained during in vitro differentiation of adult rabbit muscle-derived stem cells. Cisplatin induced apoptotic cell death. During 24-hr cisplatin treatment gradual, strong and prolonged increase of both JNK and its target protein c-Jun phosphorylation was found in ADC. Pre-treatment of cells with SP600125 decreased cisplatin-induced activation of c-Jun and promoted apoptosis. Upregulation of proapoptotic Bax and downregulation of antiapoptotic Bcl-2 proteins were found to be regulated in JNK-dependent manner. Thus, the results prove the antiapoptotic role of activated JNK in adipocyte-like cells treated with cisplatin.

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A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

Cited by 35 publications

References 56 publications

Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling

Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling

JNK-Mediated SREBP-2 Processing by Genistein up-regulates LDLR Expression in HepG2 Cells

JNK implication in adipocyte-like cell death induced by chemotherapeutic drug cisplatin

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