Stimulation of Lipogenesis by Interleukin-6 and Misoprostol-Free Acid in Isolated Rat Hepatocytes†

Brass, Eric P.; Vetter, W

doi:10.1097/00045391-199509000-00019

Cited by 6 publications

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“…The direct effect of IL-6 on STAT3 activation and subsequent upregulation of lipogenic enzymes was also confirmed in HepG2 culture. This last finding was consistent with other studies showing the stimulation of lipogenesis through IL-6 in hepatocytes ( Brass and Vetter, 1995 ). Furthermore, the upregulation of Acaca and Fasn expression by STAT3 overactivity in the liver has been reported previously ( Kinoshita et al, 2008 ).…”

Section: Discussionsupporting

confidence: 94%

“…The involvement of IL-6 in promoting fatty acid synthesis (lipogenesis) has also been observed in hepatocytes ( Brass and Vetter, 1994 , 1995 ). The synthesis of fatty acids is primarily mediated through acetyl-CoA carboxylase (isoforms ACCα and ACCβ), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) ( Strable and Ntambi, 2010 ).…”

Section: Introductionmentioning

confidence: 92%

“…Increased IL-6 plasma levels were correlated with metabolic syndrome ( Bastard et al, 2000 ; Glund and Krook, 2008 ; Kern et al, 2001 ; Mohamed-Ali et al, 1997 ), but the involvement of IL-6 in the molecular mechanisms underlying the metabolic syndrome effects is not fully understood ( Matthews et al, 2010 ; Nieto-Vazquez et al, 2008 ; Senn et al, 2002 ). Regarding the hepatic lipid metabolism, there is evidence that IL-6 affects the opposing fatty acid pathways: degradation and synthesis ( Brass and Vetter, 1994 , 1995 ; Hong et al, 2004 ; Kelly et al, 2009 ; Vida et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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

Vida

Gavito

Pavón

et al. 2015

Disease Models &Amp; Mechanisms

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Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6−/−) mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Vida

Gavito

Pavón

et al. 2015

Disease Models &Amp; Mechanisms

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“…Likewise, an IL‐6 circadian rhythm in rats and humans has also been described, although its association with the feeding/fasting cycle has not been established (Li et al , ; Vgontzas et al , ). Also, the relationship between IL‐6 and hepatic lipid metabolism, particularly in fatty acid oxidation and lipogenesis, has previously been demonstrated in vivo and in hepatocyte culture (Brass and Vetter, ; Brass and Vetter, ; Grunfeld et al , ; Hong et al , ; Vida et al , ; Vida et al , ).…”

Section: Discussionmentioning

confidence: 84%

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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“…Compared to mice fed NC, mice fed diets with the highest sugar content (WD-L, WD-C, and FD) had the greatest liver lipid content and tumor burden. Since insulin and IL-6 are potent activators of lipogenesis [44, 45], one possible scenario is that high sugar consumption coupled with elevated postprandial insulin and IL-6 expression provide the stimuli to promote tumor growth. The concept that lipogenesis is an important driver of cancer progression has been suggested previously [14, 46, 47].…”

Section: Discussionmentioning

confidence: 99%

Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

Healy¹,

Chow²,

Byrne³

et al. 2015

Journal of Hepatology

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Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.

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Stimulation of Lipogenesis by Interleukin-6 and Misoprostol-Free Acid in Isolated Rat Hepatocytes†

Cited by 6 publications

References 0 publications

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

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

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

Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

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