Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2015, Article ID 956854, 12 pages
Research Article

Cholesterol-Induced Hepatic Inflammation Does Not Underlie the Predisposition to Insulin Resistance in Dyslipidemic Female LDL Receptor Knockout Mice

1Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands
2Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands
3Academic Medical Center, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands
4Department of Molecular Genetics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, Netherlands

Received 30 November 2014; Revised 10 February 2015; Accepted 14 February 2015

Academic Editor: Kazuya Yamagata

Copyright © 2015 Nanda Gruben et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition towards insulin resistance in low-density lipoprotein receptor knock-out (Ldlr−/−) mice. For this, wild type (WT) and Ldlr−/− mice were fed a chow diet, a high fat (HF) diet, or a high fat, high cholesterol (HFC) diet for 2 weeks. Plasma lipid levels were elevated in chow-fed Ldlr−/− mice compared to WT mice. Although short-term HF or HFC feeding did not result in body weight gain and adipose tissue inflammation, dyslipidemia was worsened in Ldlr−/− mice compared to WT mice. In addition, dyslipidemic HF-fed Ldlr−/− mice had a higher hepatic glucose production rate than HF-fed WT mice, while peripheral insulin resistance was unaffected. This suggests that HF-fed Ldlr−/− mice suffered from hepatic insulin resistance. While HFC-fed Ldlr−/− mice displayed the anticipated increased hepatic inflammation, this did neither exacerbate systemic nor hepatic insulin resistance. Therefore, our results show that hepatic insulin resistance is unrelated to cholesterol-induced hepatic inflammation in Ldlr−/− mice, indicating that hepatic inflammation may not contribute to metabolic dysfunction per se.