title: Cholesterol-induced hepatic inflammation does not underlie the predisposition to insulin resistance in dyslipidemic female LDL receptor knockout mice.
abstract: 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.
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Nanda
authors: N
authors: Gruben
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Anouk
authors: A
authors: Funke
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Niels J
authors: NJ
authors: Kloosterhuis
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Marijke
authors: M
authors: Schreurs
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Fareeba
authors: F
authors: Sheedfar
authors: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands.
authors: Rick
authors: R
authors: Havinga
authors: Academic Medical Center, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
authors: Sander M
authors: SM
authors: Houten
authors: Department of Molecular Genetics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, Netherlands.
authors: Ronit
authors: 0000-0002-6736-7814
authors: R
authors: Shiri-Sverdlov
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Bart
authors: B
authors: van de Sluis
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Jan Albert
authors: JA
authors: Kuivenhoven
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Debby P Y
authors: DP
authors: Koonen
authors: Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, Netherlands.
authors: Marten H
authors: MH
authors: Hofker
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000009:adverse effects* / Q000097:blood; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D008055:Lipids; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol