TY  - JOUR
A1  - Henkel, Janin
A1  - Coleman, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weber, Daniela
A1  - Castro, Jose Pedro
A1  - Hugo, Martin
A1  - Schulz, Tim Julius
A1  - Krämer, Stephanie
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol
JF  - Molecular medicine
N2  - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
KW  - Nonalcoholic Steatohepatitis (NASH)
KW  - Typical Western Diet
KW  - Nonalcoholic Fatty Liver Disease (NAFLD)
KW  - Dietary Cholesterol
KW  - Kupffer Cells
Y1  - 2017
U6  - https://doi.org/10.2119/molmed.2016.00203
SN  - 1076-1551
SN  - 1528-3658
VL  - 23
SP  - 70
EP  - 82
PB  - Feinstein Inst. for Medical Research
CY  - Manhasset
ER  - 
TY  - JOUR
A1  - Neuschaefer-Rube, Frank
A1  - Schraplau, Anne
A1  - Schewe, Bettina
A1  - Lieske, Stefanie
A1  - Kruetzfeldt, Julia-Mignon
A1  - Ringel, Sebastian
A1  - Henkela, Janin
A1  - Birkenfeld, Andreas L.
A1  - Püschel, Gerhard Paul
T1  - Arylhydrocarbon receptor-dependent mIndy (SIc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes
JF  - Toxicology
N2  - Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, beta-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). mINDY ablation protects against diet-induced steatosis whereas mINDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the mINDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the mINDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the mINDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the mINDY promoter by benzo[a]pyrene. This study thus identified the mINDY as an AhR target gene. AhR-dependent induction of the mINDY gene might contribute to the development of hepatic steatosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
KW  - SLC13A5
KW  - Non-alcoholic fatty liver disease
KW  - NAFLD
Y1  - 2015
U6  - https://doi.org/10.1016/j.tox.2015.08.007
SN  - 0300-483X
VL  - 337
SP  - 1
EP  - 9
PB  - Elsevier
CY  - Clare
ER  -