Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells

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Abstract

Lipid-induced toxicity is part of several human diseases, but the mechanisms involved are not fully understood. Fatty liver is characterized by the expression of different growth and tissue factors. The neurotrophin, nerve growth factor (NGF) and its pro-form, pro-NGF, are present in fatty liver together with p75 neurotrophin receptor (p75NTR). Stimulation of human Huh7 hepatocyte cells with NGF and pro-NGF induced Sterol-regulator-element-binding protein-2 (SREBP2) activation and increased Low-Density Lipoprotein Receptor (LDLR) expression. We observed that phosphorylation of caspase-2 by p38 MAPK was essential for this regulation involving a caspase-3-mediated cleavage of SREBP2. RNA sequencing showed that several genes involved in lipid metabolism were altered in p75NTR-deficient mouse liver. The same lipogenic genes were downregulated in p75NTR gene-engineered human Huh7 cells and reciprocally upregulated by stimulation of p75NTRs. In the knock-out mice the serum cholesterol and triglyceride levels were reduced, suggesting a physiological role of p75NTRs in whole-body lipid metabolism. Taken together, this study shows that p75NTR signaling influences a network of genes involved in lipid metabolism in liver and hepatocyte cells. Modulation of p75NTR signaling may be a target to consider in various metabolic disorders accompanied by increased lipid accumulation.

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Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

Jing-Jing Xu, David J. B. Lloyd, Clarence Hale … (2009)

OBJECTIVE—Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model. RESEARCH DESIGN AND METHODS—DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS—FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity. CONCLUSIONS—FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.

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Phosphate-binding tag, a new tool to visualize phosphorylated proteins.

Eiji Kinoshita, Emiko Kinoshita-Kikuta, Kei Takiyama … (2006)

We introduce two methods for the visualization of phosphorylated proteins using alkoxide-bridged dinuclear metal (i.e. Zn(2+) or Mn(2+)) complexes as novel phosphate-binding tag (Phos-tag) molecules. Both Zn(2+)- and Mn(2+)-Phos-tag molecules preferentially capture phosphomonoester dianions bound to Ser, Thr, and Tyr residues. One method is based on an ECL system using biotin-pendant Zn(2+)-Phos-tag and horseradish peroxidase-conjugated streptavidin. We demonstrate the electroblotting analyses of protein phosphorylation status by the phosphate-selective ECL signals. Another method is based on the mobility shift of phosphorylated proteins in SDS-PAGE with polyacrylamide-bound Mn(2+)-Phos-tag. Phosphorylated proteins in the gel are visualized as slower migration bands compared with corresponding dephosphorylated proteins. We demonstrate the kinase and phosphatase assays by phosphate affinity electrophoresis (Mn(2+)-Phos-tag SDS-PAGE).

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Decoding cell death signals in liver inflammation.

Catherine Brenner, Lorenzo Galluzzi, Oliver Kepp … (2013)

Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Author and article information

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Dan Lindholm: +358-2941 25400 , dan.lindholm@helsinki.fi

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 11 July 2019

Publication date PMC-release: 11 July 2019

Publication date Collection: July 2019

Volume: 10

Issue: 7

Electronic Location Identifier: 537

Affiliations

[1 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, , University of Helsinki, ; POB 63, FI-00014 Helsinki, Finland

[2 ]GRID grid.452540.2, Minerva Foundation Institute for Medical Research, ; Biomedicum 2, Tukholmankatu 8, FI-00290 Helsinki, Finland

[3 ]HiLiFE, Meilahti Clinical Proteomics Core Facility, Helsinki, Finland

Author information

Vesa M. Olkkonen http://orcid.org/0000-0001-5553-7997

Maciej Lalowski http://orcid.org/0000-0002-3683-4096

Article

Publisher ID: 1758

DOI: 10.1038/s41419-019-1758-z

PMC ID: 6624261

PubMed ID: 31296846

SO-VID: 56c42a14-c8de-4cb0-a326-89861108bf36

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 13 November 2018

Date accepted : 11 June 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100005878, Suomen Akatemia | Terveyden Tutkimuksen Toimikunta (Research Council for Health);

Funded by: FundRef https://doi.org/10.13039/501100004155, Magnus Ehrnroothin Säätiö (Magnus Ehrnrooth Foundation);

Funded by: FundRef https://doi.org/10.13039/501100004191, Novo Nordisk;

Funded by: FundRef https://doi.org/10.13039/501100009708, Novo Nordisk Fonden (Novo Nordisk Foundation);

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ScienceOpen disciplines: Cell biology

Keywords: lipid signalling,metabolic disorders

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ScienceOpen disciplines: Cell biology

Keywords: lipid signalling, metabolic disorders

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Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells

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Most cited references 42

Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

Phosphate-binding tag, a new tool to visualize phosphorylated proteins.

Decoding cell death signals in liver inflammation.

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