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Int J Mol Sci. 2014 Apr 4;15(4):5762-73. doi: 10.3390/ijms15045762.

Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma.

Author information

1
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. s.kessler@mx.uni-saarland.de.
2
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. yvette.simon84@gmail.com.
3
Department of Pharmacy, Pharmaceutical Biotechnology, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), 66123 Saarbrücken, Germany. Katja.Gemperlein@helmholtz-hzi.de.
4
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. gianmoena@ifado.de.
5
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. cadenas@ifado.de.
6
Department of Medicine II, Saarland University Medical Center, Kirrberger Str., 66421 Homburg, Germany. Vincent.Zimmer@uniklinikum-saarland.de.
7
Institute of Pathology, Saarland University, Kirrberger Str., 66421 Homburg, Germany. juliane.pokorny@uniklinikum-saarland.de.
8
Center for Bioinformatics, Saarland University, Campus E2 1, 66123 Saarbrücken, Germany. barghash@bioinformatik.uni-saarland.de.
9
Center for Bioinformatics, Saarland University, Campus E2 1, 66123 Saarbrücken, Germany. volkhard.helms@bioinformatik.uni-saarland.de.
10
Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. nvanrooijen@clodronateliposomes.org.
11
Institute of Pathology, Saarland University, Kirrberger Str., 66421 Homburg, Germany. rainer.bohle@uniklinikum-saarland.de.
12
Department of Medicine II, Saarland University Medical Center, Kirrberger Str., 66421 Homburg, Germany. Frank.Lammert@uniklinikum-saarland.de.
13
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. hengstler@ifado.de.
14
Department of Pharmacy, Pharmaceutical Biotechnology, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), 66123 Saarbrücken, Germany. rom@mx.uni-saarland.de.
15
Institute of Pathology, Medical University of Graz, 8010 Graz, Austria. johannes.haybaeck@medunigraz.at.
16
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. pharm.bio.kiemer@mx.uni-saarland.de.

Abstract

Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice). Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD)-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h) increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.

PMID:
24714086
PMCID:
PMC4013594
DOI:
10.3390/ijms15045762
[Indexed for MEDLINE]
Free PMC Article

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