TY  - JOUR
AB  - 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.
AU  - von Loeffelholz, C.*
AU  - Döcke, S.*
AU  - Lock, J.F.*
AU  - Lieske, S.*
AU  - Horn, P.*
AU  - Kriebel, J.
AU  - Wahl, S.
AU  - Singmann, P.
AU  - de Las Heras Gala, T.
AU  - Grallert, H.
AU  - Raschzok, N.*
AU  - Sauer, I.M.*
AU  - Heller, R.*
AU  - Jahreis, G.*
AU  - Claus, R.A.*
AU  - Bauer, M.*
AU  - Stockmann, M.*
AU  - Birkenfeld, A.L.*
AU  - Pfeiffer, A.F.H.*
C1  - 50161
C2  - 42224
CY  - Hoboken
SP  - 890-901
TI  - Increased lipogenesis in spite of upregulated hepatic 5'AMP-activated protein kinase in human non-alcoholic fatty liver.
JO  - Hepatol. Res.
VL  - 47
IS  - 9
PB  - Wiley
PY  - 2017
SN  - 1386-6346
ER  -