Background/Aims
We determined the effects of dietary lipid composition on steatohepatitis development
with particular attention to the nature of lipid molecules that accumulate in the
liver and pathways of hepatic triglyceride synthesis.
Methods
Mice were fed methionine and choline deficient (MCD) diets supplemented with 20% fat
as lard (saturated) or olive oil (monounsaturated), for 3 weeks.
Results
Irrespective of dietary lipid composition, MCD-fed mice developed steatosis, ballooning
degeneration and lobular inflammation. MCD-feeding increased hepatic free fatty acid
(FFA) levels 2–3-fold, as well as total triglyceride levels. Hepatic FFA composition
was characterized by increased ratio of monounsaturated: saturated FFA. There were
reduced nuclear levels of the lipogenic transcription factor sterol regulatory element
binding protein-1 in MCD-fed mice, but no consistent reduction in fatty acid synthesis
genes (acetyl-CoA carboxylase and fatty acid synthase). Consistent with pathways of
hepatic triglyceride synthesis, expression of diacylglycerol acyltransferase-1 and
-2 was increased, as were delta-5- and delta-6- fatty acid desaturase mRNA levels.
Conclusions
In this nutritional model of steatohepatitis, accumulation of FFA occurs despite substantial
suppression of lipogenesis and induction of triglyceride synthesis genes. Accumulation
of FFA supports a lipotoxicity mechanism for liver injury in this form of fatty liver
disease.
Abbreviations:
ACC (acetyl-CoA carboxylase), DGAT (diacylglycerol acyltransferase), FAS (fatty acid synthase), FFA (free fatty acid), JNK (c-Jun N-terminal kinase), MCD (methionine and choline deficient), MUFA (monounsaturated fatty acid), NAFLD (non-alcoholic fatty liver disease), NAS (NAFLD activity score), NASH (non-alcoholic steatohepatitis), SCD (stearoyl-CoA desaturase), SFA (saturated fatty acid), SREBP (sterol regulatory element binding protein)Keywords
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Article info
Publication history
Published online: January 28, 2008
Accepted:
December 24,
2007
Received in revised form:
December 3,
2007
Received:
October 14,
2007
Associate Editor: Y.M. DeugnierFootnotes
☆The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the materials involved either in the past or present and they did not receive funding from the manufacturers to carry out their research.
Identification
Copyright
© 2008 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
