Hepatic mitochondrial and ER stress induced by defective PPARα signaling in the pathogenesis of hepatic steatosis

Qiaozhu Su, Chris Baker, Patricia Christian, Mark Naples, Xuedong Tong, Kezhong Zhang, Miklos Santha, Khosrow Adeli

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Emerging evidence demonstrates a close interplay between disturbances in mitochondrial function and ER homeostasis in the development of the metabolic syndrome. The present investigation sought to advance our understanding of the communication between mitochondrial dysfunction and ER stress in the onset of hepatic steatosis in male rodents with defective peroxisome proliferator-activated receptor-α (PPARα) signaling. Genetic depletion of PPARα or perturbation of PPARα signaling by high-fructose diet compromised the functional activity of metabolic enzymes involved in mitochondrial fatty acid β-oxidation and induced hepatic mitochondrial stress in rats and mice. Inhibition of PPARα activity further enhanced the expression of apolipoprotein B (apoB) mRNA and protein, which was associated with reduced mRNA expression of the sarco/endoplasmic reticulum calcium ATPase (SERCA), the induction of hepatic ER stress, and hepatic steatosis. Restoration of PPARα activity recovered the metabolic function of the mitochondria and ER, alleviated systemic hypertriglyceridemia, and improved hepatic steatosis. These findings unveil novel roles for PPARα in mediating stress signals between hepatic subcellular stress-responding machinery and in the onset of hepatic steatosis under conditions of metabolic stress.

Original languageEnglish (US)
Pages (from-to)E1264-E1273
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number11
StatePublished - Jun 1 2014


  • Apolipoprotein B
  • Endoplasmic reticulum
  • Hepatic steatosis
  • Mitochondrial and endoplasmic reticulum stress
  • Peroxisome proliferator-activated receptor-α
  • Very-low density lipoprotein

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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