Abstract
ABSTRACTInterleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6−/−) mice. Additionally, HFD-fed IL-6−/− mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6−/− mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6−/− mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.
Highlights
The authors report that high-fat diet (HFD)-fed IL-6–/– mice treated with exogenous IL-6 showed increased signal transducer and activator of transcription-3 (STAT3) activity, which has previously been associated with enhanced hepatic lipogenic enzyme expression
The deficiency in Scd1 has been reported to confer protection from steatosis, reflecting a decrease in lipogenic rates and an increase in β-oxidation pathway activation (Gutierrez-Juarez et al, 2006; Miyazaki et al, 2007). This scenario is in line with the notion that the input of excess fatty acids from the diet is equilibrated through the prioritization of the fatty acid oxidation versus lipogenesis in fatty liver
In agreement with previous studies, the HFD-derived effects were aggravated in IL-6-deficient mice, which showed higher weight gain, higher liver fat content associated with severe steatosis, higher cholesterol levels, and decreased TG levels in serum, further supporting the notion that IL-6 is involved in modulating the levels of lipid parameters in the liver and serum (El-Assal et al, 2004; Hong et al, 2004; Kroy et al, 2010; Matthews et al, 2010; Yamaguchi et al, 2010)
Summary
High fat diet (HFD)-induced obesity is the most common cause of fatty liver disease (Ciapaite et al, 2011; Vuppalanchi and Chalasani, 2009), and is related to changes in the expression of enzymes controlling lipid metabolism in the liver and adipose tissue (Shillabeer et al, 1990; Strable and Ntambi, 2010). Increased IL-6 plasma levels were correlated with metabolic syndrome (Bastard et al, 2000; Glund and Krook, 2008; Kern et al, 2001; Mohamed-Ali et al, 1997), but the involvement of IL-6 in the molecular mechanisms underlying the metabolic syndrome effects is not fully understood (Matthews et al, 2010; Nieto-Vazquez et al, 2008; Senn et al, 2002). Regarding the hepatic lipid metabolism, there is evidence that IL-6 affects the opposing fatty acid pathways: degradation and synthesis (Brass and Vetter, 1994, 1995; Hong et al, 2004; Kelly et al, 2009; Vida et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
