Tumor necrosis factor-alpha stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase.

Published

Journal Article

The mechanism by which genes involved in cholesterol biosynthesis and import are preferentially up-regulated in response to sterol depletion was elucidated with the cloning of sterol regulatory element binding protein-1 (SREBP-1). SREBP-1 is a transcription factor whose entry into the nucleus is gated by sterol-regulated proteolysis. We have investigated the role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of SREBP-1 maturation in human hepatocytes. TNF-alpha is capable of inducing SREBP-1 maturation in a time- and dose-dependent manner that is consistent with the kinetics of TNF-alpha-mediated activation of neutral sphingomyelinase (N-SMase). Antibodies to N-SMase inhibit TNF-alpha-induced SREBP-1 maturation suggesting that N-SMase is a necessary component of this signal transduction pathway. Ceramide, a product of sphingomyelin hydrolysis, is also capable of inducing SREBP-1 maturation. The mature form of SREBP-1 generated by TNF-alpha, sphingomyelinase or ceramide treatment translocates to the nucleus and binds the sterol regulatory element. This promotes transcription of the gene upstream of the sterol regulatory element. A unique finding of our studies is that ceramide stimulated SREBP-1 maturation even in the presence of cholesterol and 25-hydroxycholesterol both of which are known suppressors of SREBP-1 maturation. Our findings indicate that ceramide-mediated maturation of SREBP-1 maturation is a novel sterol-independent mechanism by which cholesterol homeostasis may be regulated.

Full Text

Duke Authors

Cited Authors

  • Lawler, JF; Yin, M; Diehl, AM; Roberts, E; Chatterjee, S

Published Date

  • February 27, 1998

Published In

Volume / Issue

  • 273 / 9

Start / End Page

  • 5053 - 5059

PubMed ID

  • 9478955

Pubmed Central ID

  • 9478955

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.273.9.5053

Language

  • eng

Conference Location

  • United States