title: IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis.
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-1β. 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 β-hydroxybutyrate levels or lipid profiles due to clodronate-treatment, but hepatic cytokine gene expressions including IL-1β were decreased. Conversely, treatment of primary mouse hepatocytes with IL-1β 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-1β signaling upregulates hepatic lipogenesis in obesity, and is essential for the induction of pathogenic hepatic steatosis in obese mice.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Negrin
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Marina T
authors.initials: MT
authors.lastname: DiStefano
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Anouch
authors.initials: A
authors.lastname: Matevossian
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America; Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America; Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: DaeYoung
authors.initials: D
authors.lastname: Jung
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America; Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D000818:Animals; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007728:Kupffer Cells; D050155:Lipogenesis / Q000235:genetics*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D054890:Fatty Acid Synthase, Type I