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.
Keywords: diethylnitrosamine; ELOVL6; HCC; hepatic steatosis; leptin deficiency; MCD; non-alcoholic fatty liver disease (NAFLD); ob/ob
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Kessler, S.M.; Simon, Y.; Gemperlein, K.; Gianmoena, K.; Cadenas, C.; Zimmer, V.; Pokorny, J.; Barghash, A.; Helms, V.; van Rooijen, N.; Bohle, R.M.; Lammert, F.; Hengstler, J.G.; Mueller, R.; Haybaeck, J.; Kiemer, A.K. Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma. Int. J. Mol. Sci. 2014, 15, 5762-5773.
Kessler SM, Simon Y, Gemperlein K, Gianmoena K, Cadenas C, Zimmer V, Pokorny J, Barghash A, Helms V, van Rooijen N, Bohle RM, Lammert F, Hengstler JG, Mueller R, Haybaeck J, Kiemer AK. Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2014; 15(4):5762-5773.
Kessler, Sonja M.; Simon, Yvette; Gemperlein, Katja; Gianmoena, Kathrin; Cadenas, Cristina; Zimmer, Vincent; Pokorny, Juliane; Barghash, Ahmad; Helms, Volkhard; van Rooijen, Nico; Bohle, Rainer M.; Lammert, Frank; Hengstler, Jan G.; Mueller, Rolf; Haybaeck, Johannes; Kiemer, Alexandra K. 2014. "Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma." Int. J. Mol. Sci. 15, no. 4: 5762-5773.