Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high fat diet-induced steatosis in IL-6 deficient mice

Vida, Margarita; Gavito, Ana Luisa; Pavón, Francisco Javier; Bautista, Dolores; Serrano, Antonia; Suárez, Juan; Arrabal, Sergio; Decara, Juan; Romero-Cuevas, Miguel; Fonseca, Fernando Rodrı́guez de; Baixerás, Elena

doi:10.1242/dmm.019166

Cited by 38 publications

(57 citation statements)

References 50 publications

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“…In contrast, low‐dose application of murine IL‐6 in mice leads to hepatic steatosis . Subchronic IL‐6 administration in IL‐6‐deficient mice exacerbated hepatic steatosis by increasing lipogenesis . Importantly, neutralization of IL‐6 with neutralizing antibodies in HFD‐fed mice improved glucose tolerance and ameliorated liver fat content .…”

Section: Discussionmentioning

confidence: 99%

“…(44) Subchronic IL-6 administration in IL-6-deficient mice exacerbated hepatic steatosis by increasing lipogenesis. (45) Importantly, neutralization of IL-6 with neutralizing antibodies in HFD-fed mice improved glucose tolerance and ameliorated liver fat content. (46) Long-term IL-6 incubation of rat hepatocytes increased lipid synthesis, and intraperitoneal IL-6 administration in mice stimulated hepatic lipogenesis by increasing hepatic citrate (47) and acetyl-coenzyme A concentrations.…”

Section: Discussionmentioning

confidence: 99%

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The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism

et al. 2017

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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 and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In non-human primates, a two 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 via the IL-6-receptor (IL-6R) and activation of the transcription factor Stat3 and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-Stat3 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 non-human primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 via mINDY. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism

et al. 2017

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“…Based on previous protocols for rIL‐6 administration (Vida et al , ; Wallenius et al , ), the WT and IL‐6 −/− mice were deprived of food at 08:00 h and treated with 3.2 ng⋅g −1 of murine rIL‐6 (Peprotech, Inc., Rocky Hill, NJ, USA ) or vehicle alone (0.1% BSA in PBS) i.p. ( n = 8 per group).…”

Section: Methodsmentioning

confidence: 99%

“…In this regard, we recently reported that recombinant IL‐6 (rIL‐6) treatment in hepatocytes induced the transcription of the PPARα target gene for carnitine palmitoyltransferase 1 ( Cpt1 ) whose protein promotes fatty acid β‐oxidation in the mitochondria (Vida et al , ). On the other hand, the biological activity of IL‐6 has also been associated with the promotion of lipogenesis and triglyceride secretion in hepatocytes (Brass and Vetter, ; Grunfeld et al , ; Vida et al , ). Moreover, and in contrast with previous findings (Hong et al , ; Reddy and Hashimoto, ), we recently showed that chronic administration of IL‐6 strikingly up‐regulated the expression of the lipogenic enzymes in the liver of IL‐6 −/− mice fed a high‐fat diet, and this was associated with aggravated hepatic steatosis (Vida et al , ).…”

Section: Introductionmentioning

confidence: 99%

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

Gavito

Cabello

Suárez

et al. 2016

British J Pharmacology

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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

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“…The HFD-derived effects were aggravated in IL-6-deficient mice: higher cholesterol levels and decreased TG levels in serum. In the context of HFD-induced obesity, the DONG, CHEN, YANG, LI, GAO, HE HUANG, LIU, GUO, CHANG, XIA, XU administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis [13] . IL-6 is considered as an anti-inflammatory cytokine through its inhibitory effects on TNF-α [14,15] .…”

Section: Discussionmentioning

confidence: 99%

Yüksek Yağlı Diyet ve Kolesterolle Beslenen Farelerde Eksojen Fibroblast Büyüme Faktörü-21’in Yangı Üzerine Etkisi

Dong¹,

Chen²,

Yang³

et al. 2017

Kafkas Univ Vet Fak Derg

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: Effect of exogenous fibroblast growth factor-21 on inflammation in a high-fat diet and cholesterol mice model. Kafkas Univ Vet Fak Derg, 24 (1): 61-68, 201861-68, . DOI: 10.9775/kvfd.2017 Abstract Fibroblast Growth Factor 21 (FGF21) is a novel metabolic regulator involved in lipid utilization, and it can involve in the regulation of lipid metabolism. To determine the physiological function of FGF21 in relation to a high-fat diet (HFD) and high cholesterol, the effect of FGF21 on immune response indicators and hematological parameters was investigated. In the experiment, a total of 24 female mice were selected, 12 of which were fed with HFDs (group 1) and the other were fed with normal diet (group 2). After 30 days, the mice of two groups were respectively divided into two groups on average: 1. HFDs mice were used as model group; 2 normal diet mice were used as control group; 3. HFDs mice injection were used as model + FGF21 group; 4. normal diet injection were used as control + FGF21 group. Mice were sacrificed at 3-day intervals and the livers were isolated and analyzed. Blood was collected and analyzed for CD3 and CD19 by flow cytometry and IL-4, IL-6 and TNF-α by ELISA. Serum TG, TC, NEFA, LDL-c, and HDL-c levels were measured by automatic biochemical analyzer. Although CD3 and CD19 varied, the difference was not significant, and the levels of IL-4, IL-6, TNF-α, TC, TG LDL-c, and NEFA in the model exogenous injection FGF21 group were lower than in the model group (P<0.05). The present results indicate that exogenous FGF21 regulates IL-4, IL-6 and TNF-α and protects the liver from inflammation damage induced by high dietary fat and cholesterol. Keywords: Exogenous FGF21, High-fat diets, Cholesterol, Immunological factor Yüksek Yağlı Diyet ve Kolesterolle Beslenen Farelerde Eksojen Fibroblast Büyüme Faktörü-21'in Yangı Üzerine Etkisi ÖzetFibroblast Büyüme Faktörü 21 (FGF21) yağların kullanımında görev alan metabolik bir düzenleyicidir ve yağ metabolizmasında rol oynar. Yüksek yağlı ve kolesterollü diyet ile FGF21'in fizyolojik fonksiyonu arasındaki ilişkiyi araştırmak amacıyla FGF21'in bağışıklık cevap indikatörleri ve kan parametreleri üzerine etkisi incelendi. Çalışmada toplam 24 dişi fare kullanıldı ve bunların 12'si yüksek yağlı diyet (Grup 1) diğer 12'si ise normal diyet (Grup 2) ile beslendi. Otuz gün sonunda iki gruptaki fareler tekrar ikişer gruba bölündü; 1: Yüksek yağlı diyet ile beslenen fareler "model grup" olarak kullanıldı, 2: Normal diyet fareler "kontrol grubu" olarak kullanıldı; 3: Yüksek yağlı diyet ile beslenen ve FGF21 enjekte edilen fareler "model + FGF21 grubu" olarak kullanıldı; 4: normal ile beslenen ve FGF21 enjekte edilen fareler "kontrol + FGF21 grubu" olarak kullanıldı. Fareler 3 gün aralıkla öldürüldü ve karaciğer dokuları incelendi. Kan toplanarak CD3 ve CD19 akışkan sitometresi ve IL-4, IL-6 ve TNF-α ise ELİSA ile analiz edildi. Serum TG, TC, NEFA, LDL-c ve HDL-c seviyeleri otomatik biyokimyasal analizleyici ile ölçüldü. CD3 ve CD19 değişmekle birlikte değişim istatistiki bakım...

show abstract

Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high fat diet-induced steatosis in IL-6 deficient mice

Cited by 38 publications

References 50 publications

The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism

The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism

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

Yüksek Yağlı Diyet ve Kolesterolle Beslenen Farelerde Eksojen Fibroblast Büyüme Faktörü-21’in Yangı Üzerine Etkisi

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