Tags

Type your tag names separated by a space and hit enter

Inflammation is independent of steatosis in a murine model of steatohepatitis.
Hepatology. 2017 07; 66(1):108-123.Hep

Abstract

Obesity and alcohol consumption synergistically promote steatohepatitis, and neutrophil infiltration is believed to be associated with steatosis. However, the underlying mechanisms remain obscure. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a complex role in lipid metabolism and inflammation; therefore, the purpose of this study was to dissect its role in regulating steatosis and neutrophil infiltration in a clinically relevant mouse steatohepatitis model of 3-month high-fat diet (HFD) feeding plus a binge of ethanol (HFD-plus-binge ethanol). Hepatocyte-specific Pparg disruption reduced liver steatosis but surprisingly increased hepatic neutrophil infiltration after HFD-plus-binge ethanol. Knockout or knockdown of the PPARγ target gene, fat-specific protein 27, reduced steatosis without affecting neutrophil infiltration in this model. Moreover, hepatocyte-specific deletion of the Pparg gene, but not the fat-specific protein 27 gene, markedly up-regulated hepatic levels of the gene for chemokine (C-X-C motif) ligand 1 (Cxcl1, a chemokine for neutrophil infiltration) in HFD-plus-binge ethanol-fed mice. In vitro, deletion of the Pparg gene also highly augmented palmitic acid or tumor necrosis factor alpha induction of Cxcl1 in mouse hepatocytes. In contrast, activation of PPARγ with a PPARγ agonist attenuated Cxcl1 expression in hepatocytes. Palmitic acid also up-regulated interleukin-8 (a key chemokine for human neutrophil recruitment) expression in human hepatocytes, which was attenuated and enhanced by cotreatment with a PPARγ agonist and antagonist, respectively. Finally, acute ethanol binge markedly attenuated HFD-induced hepatic PPARγ activation, which contributed to the up-regulation of hepatic Cxcl1 expression post-HFD-plus-binge ethanol.

CONCLUSION

Hepatic PPARγ plays an opposing role in controlling steatosis and neutrophil infiltration, leading to dissociation between steatosis and inflammation; acute ethanol gavage attenuates hepatic PPARγ activation and subsequently up-regulates hepatic CXCL1/interleukin-8 expression, thereby exacerbating hepatic neutrophil infiltration. (Hepatology 2017;66:108-123).

Authors+Show Affiliations

Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD. Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD.Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

28220523

Citation

Wang, Wei, et al. "Inflammation Is Independent of Steatosis in a Murine Model of Steatohepatitis." Hepatology (Baltimore, Md.), vol. 66, no. 1, 2017, pp. 108-123.
Wang W, Xu MJ, Cai Y, et al. Inflammation is independent of steatosis in a murine model of steatohepatitis. Hepatology. 2017;66(1):108-123.
Wang, W., Xu, M. J., Cai, Y., Zhou, Z., Cao, H., Mukhopadhyay, P., Pacher, P., Zheng, S., Gonzalez, F. J., & Gao, B. (2017). Inflammation is independent of steatosis in a murine model of steatohepatitis. Hepatology (Baltimore, Md.), 66(1), 108-123. https://doi.org/10.1002/hep.29129
Wang W, et al. Inflammation Is Independent of Steatosis in a Murine Model of Steatohepatitis. Hepatology. 2017;66(1):108-123. PubMed PMID: 28220523.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inflammation is independent of steatosis in a murine model of steatohepatitis. AU - Wang,Wei, AU - Xu,Ming-Jiang, AU - Cai,Yan, AU - Zhou,Zhou, AU - Cao,Haixia, AU - Mukhopadhyay,Partha, AU - Pacher,Pal, AU - Zheng,Shusen, AU - Gonzalez,Frank J, AU - Gao,Bin, Y1 - 2017/05/18/ PY - 2016/12/05/received PY - 2017/01/30/revised PY - 2017/02/17/accepted PY - 2017/2/22/pubmed PY - 2017/9/14/medline PY - 2017/2/22/entrez SP - 108 EP - 123 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 66 IS - 1 N2 - : Obesity and alcohol consumption synergistically promote steatohepatitis, and neutrophil infiltration is believed to be associated with steatosis. However, the underlying mechanisms remain obscure. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a complex role in lipid metabolism and inflammation; therefore, the purpose of this study was to dissect its role in regulating steatosis and neutrophil infiltration in a clinically relevant mouse steatohepatitis model of 3-month high-fat diet (HFD) feeding plus a binge of ethanol (HFD-plus-binge ethanol). Hepatocyte-specific Pparg disruption reduced liver steatosis but surprisingly increased hepatic neutrophil infiltration after HFD-plus-binge ethanol. Knockout or knockdown of the PPARγ target gene, fat-specific protein 27, reduced steatosis without affecting neutrophil infiltration in this model. Moreover, hepatocyte-specific deletion of the Pparg gene, but not the fat-specific protein 27 gene, markedly up-regulated hepatic levels of the gene for chemokine (C-X-C motif) ligand 1 (Cxcl1, a chemokine for neutrophil infiltration) in HFD-plus-binge ethanol-fed mice. In vitro, deletion of the Pparg gene also highly augmented palmitic acid or tumor necrosis factor alpha induction of Cxcl1 in mouse hepatocytes. In contrast, activation of PPARγ with a PPARγ agonist attenuated Cxcl1 expression in hepatocytes. Palmitic acid also up-regulated interleukin-8 (a key chemokine for human neutrophil recruitment) expression in human hepatocytes, which was attenuated and enhanced by cotreatment with a PPARγ agonist and antagonist, respectively. Finally, acute ethanol binge markedly attenuated HFD-induced hepatic PPARγ activation, which contributed to the up-regulation of hepatic Cxcl1 expression post-HFD-plus-binge ethanol. CONCLUSION: Hepatic PPARγ plays an opposing role in controlling steatosis and neutrophil infiltration, leading to dissociation between steatosis and inflammation; acute ethanol gavage attenuates hepatic PPARγ activation and subsequently up-regulates hepatic CXCL1/interleukin-8 expression, thereby exacerbating hepatic neutrophil infiltration. (Hepatology 2017;66:108-123). SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/28220523/Inflammation_is_independent_of_steatosis_in_a_murine_model_of_steatohepatitis_ L2 - https://doi.org/10.1002/hep.29129 DB - PRIME DP - Unbound Medicine ER -