Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma.
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.
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. s.kessler@mx.uni-saarland.de.
Sonja M
SM
Kessler
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. yvette.simon84@gmail.com.
Yvette
Y
Simon
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.
Katja
K
Gemperlein
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. gianmoena@ifado.de.
Kathrin
K
Gianmoena
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. cadenas@ifado.de.
Cristina
C
Cadenas
Department of Medicine II, Saarland University Medical Center, Kirrberger Str., 66421 Homburg, Germany. Vincent.Zimmer@uniklinikum-saarland.de.
Vincent
V
Zimmer
Institute of Pathology, Saarland University, Kirrberger Str., 66421 Homburg, Germany. juliane.pokorny@uniklinikum-saarland.de.
Juliane
J
Pokorny
Center for Bioinformatics, Saarland University, Campus E2 1, 66123 Saarbrücken, Germany. barghash@bioinformatik.uni-saarland.de.
Ahmad
A
Barghash
Center for Bioinformatics, Saarland University, Campus E2 1, 66123 Saarbrücken, Germany. volkhard.helms@bioinformatik.uni-saarland.de.
Volkhard
V
Helms
Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. nvanrooijen@clodronateliposomes.org.
Nico
N
van Rooijen
Institute of Pathology, Saarland University, Kirrberger Str., 66421 Homburg, Germany. rainer.bohle@uniklinikum-saarland.de.
Rainer M
RM
Bohle
Department of Medicine II, Saarland University Medical Center, Kirrberger Str., 66421 Homburg, Germany. Frank.Lammert@uniklinikum-saarland.de.
Frank
F
Lammert
Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Ardeystr. 67, 44139 Dortmund, Germany. hengstler@ifado.de.
Jan G
JG
Hengstler
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.
Rolf
R
Mueller
Institute of Pathology, Medical University of Graz, 8010 Graz, Austria. johannes.haybaeck@medunigraz.at.
Johannes
J
Haybaeck
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany. pharm.bio.kiemer@mx.uni-saarland.de.
Alexandra K
AK
Kiemer
D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002794:Choline; D004032:Diet; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008715:Methionine; D051379:Mice; D008811:Mice, Inbred DBA; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis
C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; D005227:Fatty Acids; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D008715:Methionine; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D002794:Choline