1. Reciprocal regulation of hepatic and adipose lipogenesis by liver X receptors in obesity and insulin resistance.
- Author
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Beaven SW, Matveyenko A, Wroblewski K, Chao L, Wilpitz D, Hsu TW, Lentz J, Drew B, Hevener AL, and Tontonoz P
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Disease Models, Animal, Fatty Liver physiopathology, Glucose Clamp Technique, Homeostasis physiology, Liver X Receptors, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins physiology, Orphan Nuclear Receptors deficiency, Orphan Nuclear Receptors genetics, PPAR gamma physiology, Signal Transduction physiology, Sterol Regulatory Element Binding Proteins physiology, Transcription Factors physiology, Adipose Tissue physiology, Insulin Resistance physiology, Lipogenesis physiology, Liver physiology, Obesity physiopathology, Orphan Nuclear Receptors physiology
- Abstract
Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXRs modulate key aspects of the metabolic syndrome in mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in β cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into the complex relationships between LXR and insulin signaling., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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