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 Jun 7;8(6):e65641. doi: 10.1371/journal.pone.0065641. Print 2013.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / pathology
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • Blood Glucose / metabolism
  • Cell Size / drug effects
  • Cholesterol / blood
  • Diet, High-Fat*
  • Fatty Acids / blood
  • Fatty Liver / blood
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Fenofibrate / pharmacology
  • Gene Expression Regulation / drug effects
  • Glucose Tolerance Test
  • Hydrocarbons, Fluorinated / pharmacology
  • Insulin / blood
  • Insulin Resistance
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Orphan Nuclear Receptors / metabolism*
  • PPAR alpha / metabolism*
  • Sulfonamides / pharmacology
  • Triglycerides / blood

Substances

  • Blood Glucose
  • Fatty Acids
  • Hydrocarbons, Fluorinated
  • Insulin
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • PPAR alpha
  • Sulfonamides
  • TO-901317
  • Triglycerides
  • Cholesterol
  • Fenofibrate