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

Hepatol. Res. 47, 890-901 (2017)
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Ampk ; Nafld ; Palmitate ; Xbp; Endoplasmic-reticulum Stress; Transcription Factor Xbp1; De-novo Lipogenesis; Growth-factor 21; Insulin-resistance; Acid-metabolism; Er Stress; Tca Cycle; Disease; Autophagy
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