PuSH - Publication Server of Helmholtz Zentrum München: Increased lipogenesis in spite of upregulated hepatic 5'AMP-activated protein kinase in human non-alcoholic fatty liver.

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von Loeffelholz, C.* ; Döcke, S.* ; Lock, J.F.* ; Lieske, S.* ; Horn, P.* ; Kriebel, J. ; Wahl, S. ; Singmann, P. ; de Las Heras Gala, T. ; Grallert, H. ; Raschzok, N.* ; Sauer, I.M.* ; Heller, R.* ; Jahreis, G.* ; Claus, R.A.* ; Bauer, M.* ; Stockmann, M.* ; Birkenfeld, A.L.* ; Pfeiffer, A.F.H.*

Increased lipogenesis in spite of upregulated hepatic 5'AMP-activated protein kinase in human non-alcoholic fatty liver.

Hepatol. Res. 47, 890-901 (2017)

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Aims: Molecular adaptations in human non-alcoholic fatty liver disease (NAFLD) are incompletely understood. This study investigated the main gene categories related to hepatic de novo lipogenesis and lipid oxidation capacity. Methods: Liver specimens of 48 subjects were histologically classified according to steatosis severity. In-depth analyses were undertaken using real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Lipid profiles were analyzed by gas chromatography/flame ionization detection, and effects of key fatty acids were studied in primary human hepatocytes. Results: Real-time polymerase chain reaction, immunoblotting, and immunohistochemistry indicated 5'AMP-activated protein kinase (AMPK) to be increased with steatosis score≥2 (all P< 0.05), including various markers of de novo lipogenesis and lipid degradation (all P< 0.05). Regarding endoplasmic reticulum stress, X-Box binding protein-1 (XBP1) was upregulated in steatosis score≥2 (P=0.029) and correlated with plasma palmitate (r=0.34; P=0.035). Palmitate incubation of primary human hepatocytes increased XBP1 and downstream stearoyl CoA desaturase-1 mRNA expression (both P< 0.05). Moreover, plasma and liver tissue exposed a NAFLD-related lipid profile with reduced polyunsaturated/saturated fatty acid ratio, increased palmitate and palmitoleate, and elevated lipogenesis and desaturation indices with steatosis score≥2 (all P< 0.05). Conclusion: In humans with advanced fatty liver disease, hepatic AMPK protein is upregulated, potentially in a compensatory manner. Moreover, pathways of lipid synthesis and degradation are co-activated in subjects with advanced steatosis. Palmitate may drive lipogenesis by activating XBP1-mediated endoplasmic reticulum stress and represent a target for future dietary or pharmacological intervention.

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