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

Su, Q. and Baker, C. and Christian, P. and Naples, M. and Tong, X. and Sántha, Miklós (2014) Hepatic mitochondrial and ER stress induced by defective PPARalpha signaling in the pathogenesis of hepatic steatosis. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 306 (11). E1264-E1273. ISSN 0193-1849

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Abstract

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-alpha (PPARalpha) signaling. Genetic depletion of PPARalpha or perturbation of PPARalpha signaling by high-fructose diet compromised the functional activity of metabolic enzymes involved in mitochondrial fatty acid beta-oxidation and induced hepatic mitochondrial stress in rats and mice. Inhibition of PPARalpha 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 PPARalpha activity recovered the metabolic function of the mitochondria and ER, alleviated systemic hypertriglyceridemia, and improved hepatic steatosis. These findings unveil novel roles for PPARalpha in mediating stress signals between hepatic subcellular stress-responding machinery and in the onset of hepatic steatosis under conditions of metabolic stress.

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