Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice.
OBJECTIVE
It is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. Several recent studies have shed doubt on this view, which questions the causality of this association. This study focuses on Kupffer cell-mediated hepatic inflammation as a possible driver of insulin resistance in the absence and presence of obesity.


METHODS
We used male mice deficient for the low-density lipoprotein receptor (Ldlr(-/-)) and susceptible to cholesterol-induced hepatic inflammation. Whole body and hepatic insulin resistance was measured in mice fed 4 diets for 2 and 15 weeks, i.e., chow, high-fat (HF), HF-cholesterol (HFC; 0.2% cholesterol) and HF without cholesterol (HFnC). Biochemical parameters in plasma and liver were measured and inflammation was determined using immunohistochemistry and RT-PCR.


RESULTS
At 2 weeks, we did not find significant metabolic effects in either diet group, except for the mice fed a HFC diet which showed pronounced hepatic inflammation (p < 0.05) but normal insulin sensitivity. At 15 weeks, a significant increase in insulin levels, HOMA-IR, and hepatic insulin resistance was observed in mice fed a HFC, HFnC, and HF diet compared to chow-fed mice (p < 0.05). Regardless of the level of hepatic inflammation (HFC > HF, HFnC; p < 0.05) insulin resistance in mice fed HFC was no worse compared to mice on a HFnC and HF diet.


CONCLUSIONS
These data show that cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male Ldlr(-/-) mice. This study suggests that Kupffer cell-driven hepatic inflammation is a consequence, not a cause, of metabolic dysfunction in obesity.
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Anouk
A
Funke
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Marijke
M
Schreurs
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Marcela
M
Aparicio-Vergara
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Fareeba
F
Sheedfar
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Nanda
N
Gruben
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Niels J
NJ
Kloosterhuis
Maastricht University, Department of Molecular Genetics, Maastricht, The Netherlands.
Ronit
R
Shiri-Sverdlov
University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
Albert K
AK
Groen
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Bart
B
van de Sluis
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands.
Marten H
MH
Hofker
University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, The Netherlands. Electronic address: d.p.y.koonen@umcg.nl.
Debby P Y
DP
Koonen
D000821:Animal Feed; D000818:Animals; D002784:Cholesterol / Q000097:blood*; D004032:Diet; D004041:Dietary Fats; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000166:cytology; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000166:cytology; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*
D004041:Dietary Fats; D007328:Insulin; D011973:Receptors, LDL; D002784:Cholesterol
Cholesterol; Inflammation; Insulin resistance; Kupffer cells; LDLR; Liver; Obesity