UMMS Affiliation

Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes; Program in Molecular Medicine

Date

9-12-2014

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Chemicals and Drugs | Endocrine System | Endocrine System Diseases | Endocrinology

Abstract

Non-alcoholic fatty liver disease is prevalent in human obesity and type 2 diabetes, and is characterized by increases in both hepatic triglyceride accumulation (denoted as steatosis) and expression of pro-inflammatory cytokines such as IL-1beta. We report here that the development of hepatic steatosis requires IL-1 signaling, which upregulates Fatty acid synthase to promote hepatic lipogenesis. Using clodronate liposomes to selectively deplete liver Kupffer cells in ob/ob mice, we observed remarkable amelioration of obesity-induced hepatic steatosis and reductions in liver weight, triglyceride content and lipogenic enzyme expressions. Similar results were obtained with diet-induced obese mice, although visceral adipose tissue macrophage depletion also occurred in response to clodronate liposomes in this model. There were no differences in the food intake, whole body metabolic parameters, serum beta-hydroxybutyrate levels or lipid profiles due to clodronate-treatment, but hepatic cytokine gene expressions including IL-1beta were decreased. Conversely, treatment of primary mouse hepatocytes with IL-1beta significantly increased triglyceride accumulation and Fatty acid synthase expression. Furthermore, the administration of IL-1 receptor antagonist to obese mice markedly reduced obesity-induced steatosis and hepatic lipogenic gene expression. Collectively, our findings suggest that IL-1beta signaling upregulates hepatic lipogenesis in obesity, and is essential for the induction of pathogenic hepatic steatosis in obese mice.

Rights and Permissions

Citation: PLoS One. 2014 Sep 12;9(9):e107265. doi: 10.1371/journal.pone.0107265. eCollection 2014. Link to article on publisher's site

DOI of Published Version

10.1371/journal.pone.0107265

Comments

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Co-authors Kimberly Negrin and Anouch Matevossian are both doctoral students in the Interdisciplinary Graduate Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School. Matevossian is also in the MD/PhD program.

Related Resources

Link to Article in PubMed

Keywords

Fatty liver, Gene expression, Hepatocytes, Inflammation, Liposomes, Macrophages, Obesity, Steatosis

Journal Title

PloS one

PubMed ID

25216251

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

 
 

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