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


CONCLUSIONS
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.
Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.|Department of Anaesthesiology and Intensive Care, Jena University Hospital, and Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, Jena, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
Christian
C
von Loeffelholz
Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Stephanie
S
Döcke
Department of General-, Visceral-, Vascular- and Paediatric Surgery, University Hospital of Wuerzburg, Wuerzburg, Germany.
Johan F
JF
Lock
Section of Metabolic and Vascular Medicine, Medical Clinic III, University Hospital Carl Gustav Carus, Dresden, Germany.
Stefanie
S
Lieske
Department of Anaesthesiology and Intensive Care, Jena University Hospital, and Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, Jena, Germany.
Paul
P
Horn
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Jennifer
J
Kriebel
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Simone
S
Wahl
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Paula
P
Singmann
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Research Group of Diabetes Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Tonia
T
de Las Heras Gala
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Harald
H
Grallert
Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
Nathaniel
N
Raschzok
Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
Igor M
IM
Sauer
Department of Anaesthesiology and Intensive Care, Jena University Hospital, and Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, Jena, Germany.|Institute for Molecular Cell Biology, Germany, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
Regine
R
Heller
Institute of Nutrition, Friedrich Schiller University, Jena, Germany.
Gerhard
G
Jahreis
Department of Anaesthesiology and Intensive Care, Jena University Hospital, and Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, Jena, Germany.
Ralf A
RA
Claus
Department of Anaesthesiology and Intensive Care, Jena University Hospital, and Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, Jena, Germany.
Michael
M
Bauer
Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin, Berlin, Germany.
Martin
M
Stockmann
Section of Metabolic and Vascular Medicine, Medical Clinic III, University Hospital Carl Gustav Carus, Dresden, Germany.
Andreas L
AL
Birkenfeld
Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Department of Endocrinology, Diabetes, and Nutrition, Charité-Universitätsmedizin, Berlin, Germany.
Andreas F H
AFH
Pfeiffer
AMPK; NAFLD; XBP; palmitate