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Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice.
PLoS One. 2013; 8(6):e65641.Plos

Abstract

Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPARα), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPARα can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPARα agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis. Gene expression analysis in the liver showed that combined treatment increased the expression of genes involved in lipogenesis and fatty acid transport, including srebp-1c, chrebp, acc1, fas, scd1 and cd36. Histochemistry and ex vivo glycerol releasing assay showed that combined treatment accelerated lipid mobilization in adipose tissue. Combined treatment also increased the transcription of glut4, hsl, atgl and adiponectin, and decreased that of plin1, cd11c, ifnγ and leptin. Combined treatment markedly elevated the transcription of fgf21 in liver but not in adipose tissue. These results suggest that concurrent activation of LXR and PPARα as a strategy to control glucose and lipid metabolism in obesity is beneficial but could lead to elevation of lipid accumulation in the liver.

Authors+Show Affiliations

Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23762402

Citation

Gao, Mingming, et al. "Concurrent Activation of Liver X Receptor and Peroxisome Proliferator-activated Receptor Alpha Exacerbates Hepatic Steatosis in High Fat Diet-induced Obese Mice." PloS One, vol. 8, no. 6, 2013, pp. e65641.
Gao M, Bu L, Ma Y, et al. Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice. PLoS ONE. 2013;8(6):e65641.
Gao, M., Bu, L., Ma, Y., & Liu, D. (2013). Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice. PloS One, 8(6), e65641. https://doi.org/10.1371/journal.pone.0065641
Gao M, et al. Concurrent Activation of Liver X Receptor and Peroxisome Proliferator-activated Receptor Alpha Exacerbates Hepatic Steatosis in High Fat Diet-induced Obese Mice. PLoS ONE. 2013;8(6):e65641. PubMed PMID: 23762402.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice. AU - Gao,Mingming, AU - Bu,Le, AU - Ma,Yongjie, AU - Liu,Dexi, Y1 - 2013/06/07/ PY - 2012/11/15/received PY - 2013/04/26/accepted PY - 2013/6/14/entrez PY - 2013/6/14/pubmed PY - 2014/1/23/medline SP - e65641 EP - e65641 JF - PloS one JO - PLoS ONE VL - 8 IS - 6 N2 - Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPARα), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPARα can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPARα agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis. Gene expression analysis in the liver showed that combined treatment increased the expression of genes involved in lipogenesis and fatty acid transport, including srebp-1c, chrebp, acc1, fas, scd1 and cd36. Histochemistry and ex vivo glycerol releasing assay showed that combined treatment accelerated lipid mobilization in adipose tissue. Combined treatment also increased the transcription of glut4, hsl, atgl and adiponectin, and decreased that of plin1, cd11c, ifnγ and leptin. Combined treatment markedly elevated the transcription of fgf21 in liver but not in adipose tissue. These results suggest that concurrent activation of LXR and PPARα as a strategy to control glucose and lipid metabolism in obesity is beneficial but could lead to elevation of lipid accumulation in the liver. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23762402/Concurrent_activation_of_liver_X_receptor_and_peroxisome_proliferator_activated_receptor_alpha_exacerbates_hepatic_steatosis_in_high_fat_diet_induced_obese_mice_ L2 - http://dx.plos.org/10.1371/journal.pone.0065641 DB - PRIME DP - Unbound Medicine ER -