title: Hepatic mitochondrial and ER stress induced by defective PPARα signaling in the pathogenesis of hepatic steatosis.
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-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.
authors.affiliation: Program of Molecular Structure and Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska;
authors.forename: Qiaozhu
authors.initials: Q
authors.lastname: Su
authors.affiliation: Program of Molecular Structure and Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Chris
authors.initials: C
authors.lastname: Baker
authors.affiliation: Program of Molecular Structure and Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Patricia
authors.initials: P
authors.lastname: Christian
authors.affiliation: Program of Molecular Structure and Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Mark
authors.initials: M
authors.lastname: Naples
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska;
authors.forename: Xuedong
authors.initials: X
authors.lastname: Tong
authors.affiliation: Wayne State University, Detroit, Michigan; and.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Institute of Biochemistry and Biological Research Center, Hungarian Academy of Sciences, Temesvari, Szeged, Hungary.
authors.forename: Miklos
authors.initials: M
authors.lastname: Santha
authors.affiliation: Program of Molecular Structure and Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; k.adeli@utoronto.ca.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D015153:Blotting, Western; D050171:Dyslipidemias / Q000209:etiology / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005632:Fructose / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008930:Mitochondria, Liver / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D061251:Primary Cell Culture; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014461:Ultracentrifugation
chemical_list: D001055:Apolipoproteins B; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; D005632:Fructose; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: apolipoprotein B; endoplasmic reticulum; hepatic steatosis; mitochondrial and endoplasmic reticulum stress; peroxisome proliferator-activated receptor-α; very-low density lipoprotein
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