p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3

Pham, Dan Duc; Do, Hai Thi; Bruelle, Céline; Kukkonen, Jyrki P.; Eriksson, Ove; Mogollón, Isabel; Korhonen, Laura; Arumäe, Urmas; Lindholm, Dan

doi:10.1074/jbc.m116.722272

Cited by 16 publications

(28 citation statements)

References 45 publications

(69 reference statements)

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“…4 c, d, e; Additional file 6 : Figure S6). On the contrary to our results, Pham DD et al recently reported that nerve growth factor (NGF) could increase LDLR expression by stimulation of p38MAPK and activation of caspase-3 and SREBP2 cleavage in hepatocytes [ 35 ]. In this study, the activation of SREBP2 was mediated by signaling pathway triggered by ligand-activated p75NTR which were induced by p38MAPK and caspase-3.…”

Section: Discussioncontrasting

confidence: 99%

Leptin decreases the expression of low-density lipoprotein receptor via PCSK9 pathway: linking dyslipidemia with obesity

Cui

et al. 2016

J Transl Med

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BackgroundPrevious studies have suggested that people with obesity showed elevated serum levels of leptin as well as lipid dysfunction and proprotein convertase subtilisin/kexin type 9 (PCSK9) played an important role in the regulation of lipid metabolism recently. The aim of this study was to determine if leptin participated in regulating the uptake of low-density lipoproteins (LDL) in hepatocytes via PCSK9.MethodsHepG2 cells were treated with human recombinant leptin. The impact of leptin on cellular low density lipoprotein receptor (LDLR) and PCSK9 protein levels was determined by Western blot. Dil-LDL uptake assay was performed to examine the LDLR function. Specific small interfering RNAs (siRNAs) were used to interfere the expressions of target proteins.ResultsThe expression of LDLR and LDL uptake could be significantly down-regulated by leptin treatment while the expressions of PCSK9 and hepatocyte nuclear factor 1α (HNF1α) were enhanced in HepG2 cells. Furthermore, inhibition of PCSK9 or HNF1α expression by siRNAs rescued the reduction of LDLR expression and LDL uptake by leptin. We found that leptin activated the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. Moreover, the changes of the expressions of HNF1α, PCSK9, LDLR, and LDL uptake induced by leptin could be blocked by p38MAPK inhibitor (SB203580). Additionally, leptin attenuated the up-regulation of LDLR caused by atorvastatin in HepG2 cells.ConclusionsThese findings indicated firstly that leptin reduced LDLR levels in hepatocyte via PCSK9 pathway, suggesting that PCSK9 might be a alternative target for dyslipidemia in the obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1032-4) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

Leptin decreases the expression of low-density lipoprotein receptor via PCSK9 pathway: linking dyslipidemia with obesity

Cui

et al. 2016

J Transl Med

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“…We found that p75NTR, but not NGF, showed increased expression in liver samples obtained from patients with hepatolithiasis. Interestingly, not only NGF 8 but also proNGF 15 protected hepatocytes from oxidative injury in vitro , whereas blockade of either TrkA or p75NTR ameliorated the hepatoprotective effects of NGF and proNGF in vitro . Further in vivo experiments suggested that exogenous NGF administration was able to inhibit hepatocyte apoptosis in cholestatic liver injury.…”

Section: Discussionmentioning

confidence: 97%

Nerve growth factor upregulates sirtuin 1 expression in cholestasis: a potential therapeutic target

et al. 2018

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This study investigated the regulatory role of nerve growth factor (NGF) in sirtuin 1 (SIRT1) expression in cholestatic livers. We evaluated the expression of NGF and its cognate receptors in human livers with hepatolithiasis and the effects of NGF therapy on liver injury and hepatic SIRT1 expression in a bile duct ligation (BDL) mouse model. Histopathological and molecular analyses showed that the hepatocytes of human diseased livers expressed NGF, proNGF (a precursor of NGF), TrkA and p75NTR, whereas only p75NTR was upregulated in hepatolithiasis, compared with non-hepatolithiasis livers. In the BDL model without NGF therapy, p75NTR, but not TrkA antagonism, significantly deteriorated BDL-induced liver injury. By contrast, the hepatoprotective effect of NGF was abrogated only by TrkA and not by p75NTR antagonism in animals receiving NGF therapy. Intriguingly, a positive correlation between hepatic SIRT1 and NGF expression was found in human livers. In vitro studies demonstrated that NGF upregulated SIRT1 expression in mouse livers and human Huh-7 and rodent hepatocytes. Both NGF and proNGF induced protective effects against hydrogen peroxide-induced cytotoxicity in Huh-7 cells, whereas inhibition of TrkA and p75NTR activity prevented oxidative cell death. Mechanistically, NGF, but not proNGF, upregulated SIRT1 expression in human Huh-7 and rodent hepatocytes via nuclear factor (NF)-κB activity, whereas NGF-induced phosphoinositide-3 kinase/Akt, extracellular signal–regulated kinase and NF-κB signaling and SIRT1 activity were involved in its hepatoprotective effects against oxidative injury. These findings suggest that pharmacological manipulation of the NGF/SIRT1 axis might serve as a novel approach for the treatment of cholestatic disease.

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“…Whether NLRP3 inflammasome activation of caspase-1 also results in SREBP cleavage in the setting of obesity and/or NAFLD/NASH is not known; however, if cleavage results in activation of SREBP, and enhanced lipogenesis, then this is not a desirable outcome in the treatment of these metabolic diseases. Some evidence suggests that caspase-3 may cleave SREBP2 in a non-apoptotic manner in response to NGF and pro-NGF stimulation of p75 neurotrophin receptor signalling to regulate low-density lipoprotein receptors (LDLRs) and lipid uptake [95]. Although human CASP2 gene was reported to be under transcriptional control of the SREBPs and involved in positive-feedback loop, recombinant caspase-2 does not cleave SREBPs [92].…”

Section: Caspase Substrates Influencing De Novo Lipogenesis and Adipomentioning

confidence: 99%

Caspases in metabolic disease and their therapeutic potential

Wilson

Kumar

2018

Cell Death Differ

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Caspases, a family of cysteine-dependent aspartate-specific proteases, are central to the maintenance of cellular and organismal homoeostasis by functioning as key mediators of the inflammatory response and/or apoptosis. Both metabolic inflammation and apoptosis play a central role in the pathogenesis of metabolic disease such as obesity and the progression of nonalcoholic steatohepatisis (NASH) to more severe liver disease. Obesity and nonalcoholic fatty liver disease (NAFLD) are the leading global health challenges associated with the development of numerous comorbidities including insulin resistance, type-2 diabetes and early mortality. Despite the high prevalence, current treatment strategies including lifestyle, dietary, pharmaceutical and surgical interventions, are often limited in their efficacy to manage or treat obesity, and there are currently no clinical therapies for NAFLD/NASH. As mediators of inflammation and cell death, caspases are attractive therapeutic targets for the treatment of these metabolic diseases. As such, pan-caspase inhibitors that act by blocking apoptosis have reached phase I/II clinical trials in severe liver disease. However, there is still a lack of knowledge of the specific and differential functions of individual caspases. In addition, cross-talk between alternate cell death pathways is a growing concern for long-term caspase inhibition. Evidence is emerging of the important cell-death-independent, non-apoptotic functions of caspases in metabolic homoeostasis that may be of therapeutic value. Here, we review the current evidence for roles of caspases in metabolic disease and discuss their potential targeting as a therapeutic strategy.

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p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3

Cited by 16 publications

References 45 publications

Leptin decreases the expression of low-density lipoprotein receptor via PCSK9 pathway: linking dyslipidemia with obesity

Leptin decreases the expression of low-density lipoprotein receptor via PCSK9 pathway: linking dyslipidemia with obesity

Nerve growth factor upregulates sirtuin 1 expression in cholestasis: a potential therapeutic target

Caspases in metabolic disease and their therapeutic potential

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