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

Dan Duc Pham, Celine Bruelle, Hai Thi Do, Ceren Pajanoja, Congyu Jin, Vesa M. Olkkonen, Ove Eriksson-Rosenberg, Matti Jauhiainen, Maciej Lalowski, Dan Lindholm

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
Article number537
JournalCell Death and Disease
Volume10
Number of pages15
ISSN2041-4889
DOIs
Publication statusPublished - 11 Jul 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • APOPTOSIS
  • CHOLESTEROL
  • DISEASE
  • EXPRESSION
  • INJURY
  • KINASE
  • LIPOAPOPTOSIS
  • NERVE GROWTH-FACTOR
  • P75(NTR)
  • PHOSPHORYLATION
  • 1182 Biochemistry, cell and molecular biology

Cite this

@article{7574a0d2237b44469ea9d925ecb1ef37,
title = "Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells",
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.",
keywords = "APOPTOSIS, CHOLESTEROL, DISEASE, EXPRESSION, INJURY, KINASE, LIPOAPOPTOSIS, NERVE GROWTH-FACTOR, P75(NTR), PHOSPHORYLATION, 1182 Biochemistry, cell and molecular biology",
author = "Pham, {Dan Duc} and Celine Bruelle and Do, {Hai Thi} and Ceren Pajanoja and Congyu Jin and Olkkonen, {Vesa M.} and Ove Eriksson-Rosenberg and Matti Jauhiainen and Maciej Lalowski and Dan Lindholm",
year = "2019",
month = "7",
day = "11",
doi = "10.1038/s41419-019-1758-z",
language = "English",
volume = "10",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",

}

Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells. / Pham, Dan Duc ; Bruelle, Celine; Do, Hai Thi; Pajanoja, Ceren; Jin, Congyu; Olkkonen, Vesa M.; Eriksson-Rosenberg, Ove; Jauhiainen, Matti; Lalowski, Maciej; Lindholm, Dan.

In: Cell Death and Disease, Vol. 10, 537, 11.07.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells

AU - Pham, Dan Duc

AU - Bruelle, Celine

AU - Do, Hai Thi

AU - Pajanoja, Ceren

AU - Jin, Congyu

AU - Olkkonen, Vesa M.

AU - Eriksson-Rosenberg, Ove

AU - Jauhiainen, Matti

AU - Lalowski, Maciej

AU - Lindholm, Dan

PY - 2019/7/11

Y1 - 2019/7/11

N2 - 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.

AB - 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.

KW - APOPTOSIS

KW - CHOLESTEROL

KW - DISEASE

KW - EXPRESSION

KW - INJURY

KW - KINASE

KW - LIPOAPOPTOSIS

KW - NERVE GROWTH-FACTOR

KW - P75(NTR)

KW - PHOSPHORYLATION

KW - 1182 Biochemistry, cell and molecular biology

U2 - 10.1038/s41419-019-1758-z

DO - 10.1038/s41419-019-1758-z

M3 - Article

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

M1 - 537

ER -