TY - JOUR
T1 - Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice
AU - Funke, Anouk
AU - Schreurs, Marijke
AU - Aparicio-Vergara, Marcela
AU - Sheedfar, Fareeba
AU - Gruben, Nanda
AU - Kloosterhuis, Niels J.
AU - Shiri-Sverdlov, Ronit
AU - Groen, Albert K.
AU - van de Sluis, Bart
AU - Hofker, Marten H.
AU - Koonen, Debby P. Y.
PY - 2014
Y1 - 2014
N2 - 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. Conclusion: 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved
AB - 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. Conclusion: 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved
U2 - https://doi.org/10.1016/j.atherosclerosis.2013.11.074
DO - https://doi.org/10.1016/j.atherosclerosis.2013.11.074
M3 - Article
C2 - 24468153
SN - 0021-9150
VL - 232
SP - 390
EP - 396
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -