Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice

Andrew M. Miller, Hua Wang, Adeline Bertola, Ogyi Park, Norio Horiguchi, Sung Hwan Ki, Shi Yin, Fouad Lafdil, Bin Gao

Research output: Contribution to journalArticle

Abstract

Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10 -/-) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10 -/- mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10 -/- mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10 -/- mice. Conversely, IL-10 -/- mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10 -/-IL-6 -/- or IL-10 -/-STAT3 Hep-/- double knockout mice. Conclusion: IL-10 -/- mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver.

Original languageEnglish (US)
Pages (from-to)846-856
Number of pages11
JournalHepatology
Volume54
Issue number3
DOIs
StatePublished - Sep 2 2011
Externally publishedYes

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Alcoholic Fatty Liver
STAT3 Transcription Factor
Interleukin-10
Transcriptional Activation
Interleukin-6
Inflammation
Liver
High Fat Diet
Fatty Liver
Ethanol
Fatty Acids
Non-alcoholic Fatty Liver Disease
Sterol Regulatory Element Binding Protein 1
Carnitine O-Palmitoyltransferase
Acetyl-CoA Carboxylase
Adenosine Monophosphate
Knockout Mice
Protein Kinases
Genes
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Hepatology

Cite this

Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice. / Miller, Andrew M.; Wang, Hua; Bertola, Adeline; Park, Ogyi; Horiguchi, Norio; Hwan Ki, Sung; Yin, Shi; Lafdil, Fouad; Gao, Bin.

In: Hepatology, Vol. 54, No. 3, 02.09.2011, p. 846-856.

Research output: Contribution to journalArticle

Miller, Andrew M. ; Wang, Hua ; Bertola, Adeline ; Park, Ogyi ; Horiguchi, Norio ; Hwan Ki, Sung ; Yin, Shi ; Lafdil, Fouad ; Gao, Bin. / Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice. In: Hepatology. 2011 ; Vol. 54, No. 3. pp. 846-856.
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abstract = "Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5{\%} ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10 -/-) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10 -/- mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10 -/- mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10 -/- mice. Conversely, IL-10 -/- mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10 -/-IL-6 -/- or IL-10 -/-STAT3 Hep-/- double knockout mice. Conclusion: IL-10 -/- mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver.",
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T1 - Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice

AU - Miller, Andrew M.

AU - Wang, Hua

AU - Bertola, Adeline

AU - Park, Ogyi

AU - Horiguchi, Norio

AU - Hwan Ki, Sung

AU - Yin, Shi

AU - Lafdil, Fouad

AU - Gao, Bin

PY - 2011/9/2

Y1 - 2011/9/2

N2 - Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10 -/-) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10 -/- mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10 -/- mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10 -/- mice. Conversely, IL-10 -/- mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10 -/-IL-6 -/- or IL-10 -/-STAT3 Hep-/- double knockout mice. Conclusion: IL-10 -/- mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver.

AB - Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10 -/-) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10 -/- mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10 -/- mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10 -/- mice. Conversely, IL-10 -/- mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10 -/-IL-6 -/- or IL-10 -/-STAT3 Hep-/- double knockout mice. Conclusion: IL-10 -/- mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver.

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