Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes; Program in Molecular Medicine
Cellular and Molecular Physiology | Chemicals and Drugs | Endocrine System | Endocrine System Diseases | Endocrinology
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.
Fatty liver, Gene expression, Hepatocytes, Inflammation, Liposomes, Macrophages, Obesity, Steatosis
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DOI of Published Version
PLoS One. 2014 Sep 12;9(9):e107265. doi: 10.1371/journal.pone.0107265. eCollection 2014. Link to article on publisher's site
Negrin, Kimberly A.; Roth Flach, Rachel J.; DiStefano, Marina T.; Matevossian, Anouch; Friedline, Randall H.; Jung, Dae Young; Kim, Jason K.; and Czech, Michael P., "IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis" (2014). Open Access Articles. 2474.
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