Cell Type-Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury

Norio Horiguchi, Lei Wang, Partha Mukhopadhyay, Ogyi Park, Won Il Jeong, Fouad Lafdil, Douglas Osei-Hyiaman, Akira Moh, Xin Yuan Fu, Pál Pacher, George Kunos, Bin Gao

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Abstract

Background & Aims: Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure. Methods: The role of STAT3 in alcoholic liver injury was investigated in hepatocyte-specific STAT3 knockout (H-STAT3KO) mice and macrophage/neutrophil-specific STAT3 KO (M/N-STAT3KO) mice. Alcoholic liver injury was achieved by feeding mice a liquid diet containing 5% ethanol for up to 8 weeks. Results: Compared with wild-type mice, feeding H-STAT3KO mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed M/N-STAT3KO mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed H-STAT3KO mice produced similar amounts of reactive oxygen species and tumor necrosis factor α, whereas Kupffer cells from M/N-STAT3KO mice produced more reactive oxygen species and tumor necrosis factor α compared with wild-type controls. Conclusions: These findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression.

Original languageEnglish
Pages (from-to)1148-1158
Number of pages11
JournalGastroenterology
Volume134
Issue number4
DOIs
StatePublished - Apr 2008

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STAT3 Transcription Factor
Anti-Inflammatory Agents
Liver
Wounds and Injuries
Kupffer Cells
Hepatocytes
Ethanol
Macrophages
Knockout Mice
Inflammation
Neutrophils
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
Sterol Regulatory Element Binding Proteins
Alcoholic Fatty Liver
Stearoyl-CoA Desaturase
Sterol Regulatory Element Binding Protein 1
Cytokines
Diet
Acetyl-CoA Carboxylase

ASJC Scopus subject areas

  • Gastroenterology

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Cell Type-Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury. / Horiguchi, Norio; Wang, Lei; Mukhopadhyay, Partha; Park, Ogyi; Jeong, Won Il; Lafdil, Fouad; Osei-Hyiaman, Douglas; Moh, Akira; Fu, Xin Yuan; Pacher, Pál; Kunos, George; Gao, Bin.

In: Gastroenterology, Vol. 134, No. 4, 04.2008, p. 1148-1158.

Research output: Contribution to journalArticle

Horiguchi, N, Wang, L, Mukhopadhyay, P, Park, O, Jeong, WI, Lafdil, F, Osei-Hyiaman, D, Moh, A, Fu, XY, Pacher, P, Kunos, G & Gao, B 2008, 'Cell Type-Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury', Gastroenterology, vol. 134, no. 4, pp. 1148-1158. https://doi.org/10.1053/j.gastro.2008.01.016
Horiguchi, Norio ; Wang, Lei ; Mukhopadhyay, Partha ; Park, Ogyi ; Jeong, Won Il ; Lafdil, Fouad ; Osei-Hyiaman, Douglas ; Moh, Akira ; Fu, Xin Yuan ; Pacher, Pál ; Kunos, George ; Gao, Bin. / Cell Type-Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury. In: Gastroenterology. 2008 ; Vol. 134, No. 4. pp. 1148-1158.
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AU - Horiguchi, Norio

AU - Wang, Lei

AU - Mukhopadhyay, Partha

AU - Park, Ogyi

AU - Jeong, Won Il

AU - Lafdil, Fouad

AU - Osei-Hyiaman, Douglas

AU - Moh, Akira

AU - Fu, Xin Yuan

AU - Pacher, Pál

AU - Kunos, George

AU - Gao, Bin

PY - 2008/4

Y1 - 2008/4

N2 - Background & Aims: Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure. Methods: The role of STAT3 in alcoholic liver injury was investigated in hepatocyte-specific STAT3 knockout (H-STAT3KO) mice and macrophage/neutrophil-specific STAT3 KO (M/N-STAT3KO) mice. Alcoholic liver injury was achieved by feeding mice a liquid diet containing 5% ethanol for up to 8 weeks. Results: Compared with wild-type mice, feeding H-STAT3KO mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed M/N-STAT3KO mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed H-STAT3KO mice produced similar amounts of reactive oxygen species and tumor necrosis factor α, whereas Kupffer cells from M/N-STAT3KO mice produced more reactive oxygen species and tumor necrosis factor α compared with wild-type controls. Conclusions: These findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression.

AB - Background & Aims: Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure. Methods: The role of STAT3 in alcoholic liver injury was investigated in hepatocyte-specific STAT3 knockout (H-STAT3KO) mice and macrophage/neutrophil-specific STAT3 KO (M/N-STAT3KO) mice. Alcoholic liver injury was achieved by feeding mice a liquid diet containing 5% ethanol for up to 8 weeks. Results: Compared with wild-type mice, feeding H-STAT3KO mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed M/N-STAT3KO mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed H-STAT3KO mice produced similar amounts of reactive oxygen species and tumor necrosis factor α, whereas Kupffer cells from M/N-STAT3KO mice produced more reactive oxygen species and tumor necrosis factor α compared with wild-type controls. Conclusions: These findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression.

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