Role of CYP2E1 in the Progression to NASH

  • Czaja, Mark J. (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver (hepatic
steatosis) can progress by unknown mechanisms to nonalcoholic steatohepatitis
(NASH) that is characterized by hepatocyte injury and death, inflammation and
fibrosis. Both human NASH and animal models of NASH are associated with
increased expression of the pro-oxidant enzyme cytochrome P450 2E1 (CYP2E1). We
hypothesize that sustained CYP2EI expression promotes the progression from
steatosis to NASH through oxidant-mediated alterations in cell death signaling
pathways that sensitize hepatocytes to injury and death from NASH-related
cofactors such as tumor necrosis factor-a (TNF-ct) and polyunsaturated fatty
acids. To test this hypothesis we have developed novel, nontransformed
hepatocyte cell lines with differential CYP2E1 expression. Preliminary studies
have demonstrated that increased CYP2E1 expression sensitizes hepatocytes to
death stimuli in association with alterations in mitogen-activated protein
kinase signaling, transcription factor activation, and cellular glutathione
content. The goal of this proposal is to determine the molecular mechanisms by
which increased CYP2E1 expression promotes hepatocyte death, and contributes to
the progression from steatosis to NASH. The specific aims of this proposal are
to: (1) Determine the mechanism by which increased CYP2E1 expression sensitizes
hepatocytes to injury and cell death from TNF-a and polyunsaturated fatty
acids. (2) Identify AP-1 transcriptional activation as the ultimate downstream
effector of cell death in CYP2E1-expressing hepatocytes. (3) Define cellular
changes induced by CYP2E 1 expression that promote cell death from necrosis
rather than apoptosis. (4) Examine the ability of lipopolysaccharide and TNF-a
to trigger the progression to steatohepatitis in an in vivo NASH model. The
ultimate objective of these investigations is to better understand the
mechanisms leading to the progression of steatosis to steatohepatitis, in order
to develop new therapies to prevent the hepatocyte injury that underlies human
NASH.
StatusFinished
Effective start/end date5/15/026/30/17

Funding

  • National Institutes of Health: $321,617.00
  • National Institutes of Health: $302,687.00
  • National Institutes of Health: $333,494.00
  • National Institutes of Health: $330,159.00
  • National Institutes of Health: $363,225.00
  • National Institutes of Health: $321,617.00
  • National Institutes of Health: $326,857.00
  • National Institutes of Health: $314,059.00
  • National Institutes of Health: $321,617.00
  • National Institutes of Health: $363,225.00
  • National Institutes of Health: $358,225.00
  • National Institutes of Health: $60,538.00
  • National Institutes of Health: $181,600.00
  • National Institutes of Health: $333,494.00
  • National Institutes of Health: $350,513.00
  • National Institutes of Health: $340,300.00

ASJC

  • Medicine(all)

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