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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.
Alkuperäiskielienglanti
Artikkeli537
LehtiCell Death and Disease
Vuosikerta10
Sivumäärä15
ISSN2041-4889
DOI - pysyväislinkit
TilaJulkaistu - 11 heinäkuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1182 Biokemia, solu- ja molekyylibiologia

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