OMEGA-3 FATTY ACID--CCL4 INDUCED LIVER DISEASE

  • Zern, Mark A, (PI)

Project: Research project

Description

The objective of this proposal is to delineate the molecular mechanisms by
which a diet rich in omega 3 fatty acids (w 3FAs) is injurious to the
liver. Because the hepatic injury induced by fish oil may be exacerbated
by the concomitant use of another hepatotoxin, such as alcohol, both agents
will be employed to determine whether fibrogenesis is enhanced. Specific
Aims: 1) to determine the level of gene regulation by which w 3FAs alone,
and in combination with ethanol, initiate hepatic fibrogenesis; 2) to
analyze the actions of a diet rich in w3FAs and ethanol on the formation of
eicosanoids. 3) to ascertain the effects of w3FAs and ethanol
administration on fibrogenic cytokine synthesis; 4) To determine whether
the molecular mechanisms by which w3FAs and ethanol induce liver injury
differ from the mechanisms of CCl4-induced fibrosis; and 5) to delineate
the antifibrogenic effects of specific biological agents. Methods: Rats
will be fed a diet rich in w3FAs or rich in saturated fats +/- ethanol for
six months. Livers will be evaluated for collagen and other extracellular
matrix gene expression by light and electron microscopy, HPLC analysis,
Northern blot hybridization studies, and nuclear run-on assays. Eicosanoid
analysis of liver tissue will be accomplished by HPLC and RIA. The cascade
of inflammatory and fibrogenic cytokines will be investigated by biological
assays and determination of steady state mRNA levels and gene transcription
rates. The gel retardation assay and DNase I footprinting will be used to
assess differences in nuclear-binding proteins that may exist between CCl4
- induced fibrosis and injury induced by w3FAs and ethanol administration.
Biological agents such as PGE2, gamma-interferon, and neutralizing
antibodies to TGF beta or TNF alpha will be used to intervene in the
fibrogenic process. In vitro studies of hepatocytes, Ito cells, and
Kupffer cells will also evaluate the effects of w3FAs and ethanol on matrix
formation, eicosanoid metabolism, and cytokine production. Health
relatedness: The hypothesis that w3FAs may play a role in hepatic
fibrogenesis is a novel concept with important therapeutic implications; if
shown to be true, this theory would raise serious questions about the
indiscriminate use of w3FAs.
StatusFinished
Effective start/end date8/1/896/30/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Omega-3 Fatty Acids
Liver Diseases
Ethanol
Liver
Liposomes
Cytokines
Biological Factors
Diet
Fibrosis
High Pressure Liquid Chromatography
Wounds and Injuries
Electrophoretic Mobility Shift Assay
Hepatic Stellate Cells
Transforming Growth Factor alpha
Eicosanoids
Fish Oils
Northern Blotting
Deoxyribonuclease I
Nuclear Proteins
Dinoprostone

Keywords

  • Medicine(all)