PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion.
Studies have shown that decreased mitochondrial content and function are associated with hepatic steatosis. We examined whether peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) overexpression and a subsequent increase in mitochondrial content and function in rat primary hepatocytes (in vitro) and Sprague-Dawley rats (in vivo) would comprehensively alter mitochondrial lipid metabolism, including complete (CO(2)) and incomplete (acid-soluble metabolites) fatty acid oxidation (FAO), tricarboxylic acid cycle flux, and triacylglycerol (TAG) storage and export. PGC-1α overexpression in primary hepatocytes produced an increase in markers of mitochondrial content and function (citrate synthase, mitochondrial DNA, and electron transport system complex proteins) and an increase in FAO, which was accompanied by reduced TAG storage and TAG secretion compared with control. Also, the PGC-1α-overexpressing hepatocytes were protected from excess TAG accumulation following overnight lipid treatment. PGC-1α overexpression in hepatocytes lowered expression of genes critical to VLDL assembly and secretion (apolipoprotein B and microsomal triglyceride transfer protein). Adenoviral transduction of rats with PGC-1α resulted in a liver-specific increase in PGC-1α expression and produced an in vivo liver phenotype of increased FAO via increased mitochondrial function that also resulted in reduced hepatic TAG storage and decreased plasma TAG levels. In conclusion, overexpression of hepatic PGC-1α and subsequent increases in FAO through elevated mitochondrial content and/or function result in reduced TAG storage and secretion in the in vitro and in vivo milieu.
Department of Internal Medicine-Gastroenterology, University of Missouri, Columbia, Missouri, USA.
E Matthew
EM
Morris
Grace M E
GM
Meers
Frank W
FW
Booth
Kevin L
KL
Fritsche
Christopher D
CD
Hardin
John P
JP
Thyfault
Jamal A
JA
Ibdah
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*
D001055:Apolipoproteins B; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides