Single administration of recombinant IL‐6 restores the gene expression of lipogenic enzymes in liver of fasting IL‐6‐deficient mice

Abstract

Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. EXPERIMENTAL APPROACHGene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6 À/À ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. KEY RESULTSDuring feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6 À/À mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6 À/À mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6 À/À than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up-regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. CONCLUSIONS AND IMPLICATIONSIL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution. AbbreviationsACC, (Accα/β, Acaca/b) acetyl-CoA carboxylase; FAS, (Fasn) fatty acid synthase; rIL-6, recombinant IL-6; SCD1, (Scd1, Scd1) stearoyl-CoA desaturase-1; STAT3, (Stat3, Stat3) signal transducer and activator of transcription factor 3; Srebp-1c, (Srebp-1c) sterol regulatory element-binding proteins-1c

Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

“…Finally, Ppar α KO mice were also exposed to a repeated vehicle or APAP administration for 3 days ( n = 6/group). Animals were fasted for 12 h before sacrifice to avoid food-induced changes in liver genes (Vida et al, 2015 ; Gavito et al, 2016 ).…”

Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

“…For some experiments IL-6-deficient (IL-6 -/- ) mice, strain B6.129S2-IL-6 tm1Kopf /J (SN 2650, http://jaxmice.jax.org/strain/002650.html ), were also included. Since the levels of lipogenic enzymes in liver may vary depending on the time of food intake or fasting [ 36 ], both strains were maintained in the same feeding/fasting conditions. The day of sacrifice, animals were fasted from 08:00 h. The mice were treated with the last inoculation of rIL-6 or vehicle at 12:00 h and were sacrificed 1 hour later.…”

“…Interestingly, treatment of mice with IL-6 increases the levels of Stat3 mRNA in the liver [ 35 ]. Moreover, we reported that the gene expression of the lipogenic enzymes Acac, Fas and Stearoyl-CoaA desaturase (Scd1) was no longer up-regulated by IL-6 in the presence of siRNA Stat3 in hepatocytes, therefore indicating that IL-6-mediated signalling promotes the expression of these enzymes via activation of Stat3 [ 36 ].…”

“…In a recent study we observed that a single low dose of IL-6 up-regulated the gene expression of lipogenic enzymes in IL-6 -/- mice under a normal chow diet [ 36 ]. However, notably, this phenomenon was less obvious in the corresponding counterpart wild-type (WT) mice, which appeared less receptive to IL-6 treatment [ 36 ].…”

“…In a recent study we observed that a single low dose of IL-6 up-regulated the gene expression of lipogenic enzymes in IL-6 -/- mice under a normal chow diet [ 36 ]. However, notably, this phenomenon was less obvious in the corresponding counterpart wild-type (WT) mice, which appeared less receptive to IL-6 treatment [ 36 ]. Interestingly, the repeated administration of human IL-6 to WT mice causes complete remission of the fatty liver diseases [ 10 , 21 , 22 ] whereas the replacement of IL-6 in IL6 -/- mice with fatty liver aggravates the steatosis [ 12 ].…”