TY  - JOUR
A1  - von Loeffelholz, Christian
A1  - Lieske, Stefanie
A1  - Neuschaefer-Rube, Frank
A1  - Willmes, Diana M.
A1  - Raschzok, Nathanael
A1  - Sauer, Igor M.
A1  - König, Jörg
A1  - Fromm, Martin F.
A1  - Horn, Paul
A1  - Chatzigeorgiou, Antonios
A1  - Pathe-Neuschaefer-Rube, Andrea
A1  - Jordan, Jens
A1  - Pfeiffer, Andreas F. H.
A1  - Mingrone, Geltrude
A1  - Bornstein, Stefan R.
A1  - Stroehle, Peter
A1  - Harms, Christoph
A1  - Wunderlich, F. Thomas
A1  - Helfand, Stephen L.
A1  - Bernier, Michel
A1  - de Cabo, Rafael
A1  - Shulman, Gerald I.
A1  - Chavakis, Triantafyllos
A1  - Püschel, Gerhard Paul
A1  - Birkenfeld, Andreas L.
T1  - The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism
BT  - official journal of the American Association for the Study of Liver Diseases
JF  - Hepatology
N2  - Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. Conclusion: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450.
Y1  - 2017
U6  - https://doi.org/10.1002/hep.29089
SN  - 0270-9139
SN  - 1527-3350
VL  - 66
IS  - 2
SP  - 616
EP  - 630
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Camargo, Rodolfo Gonzalez
A1  - Riccardi, Daniela Mendes dos Reis
A1  - Ribeiro, Henrique Quintas Teixeira
A1  - Carnevali Junior, Luiz Carlos
A1  - Matos-Neto, Emidio Marques de
A1  - Enjiu, Lucas
A1  - Neves, Rodrigo Xavier
A1  - Lima, Joanna Darck Carola Correia
A1  - Figuerêdo, Raquel Galvão
A1  - Alcântara, Paulo Sérgio Martins de
A1  - Maximiano, Linda
A1  - Otoch, José
A1  - Batista Jr., Miguel Luiz
A1  - Püschel, Gerhard Paul
A1  - Seelaender, Marilia
T1  - NF-kappa Bp65 and expression of its pro-inflammatory target genes are upregulated in the subcutaneous adipose tissue of cachectic cancer patients
N2  - Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1β, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1β, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 349 
KW  - cancer cachexia
KW  - inflammation
KW  - white adipose tissue
KW  - NF-κB
KW  - IκB
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-400163
ER  - 
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  -