Gly482Ser mutation impairs the effects of peroxisome proliferator-activated receptor coactivator-1 on decreasing fat deposition and stimulating phosphoenolpyruvate carboxykinase expression in hepatocytes.
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abstract
Peroxisome proliferator-activated receptor coactivator-1 (PGC-1) is a transcriptional coactivator of nuclear receptor peroxisome proliferator-activated receptor that critically regulates glucose and fat metabolism. Although clinical evidence suggests that Gly482Ser polymorphism of PGC-1 is associated with an increased incidence of nonalcoholic fatty liver disease, a direct role for Gly482Ser mutation in altering PGC-1 actions on hepatocyte fat deposition remains to be explored. We hypothesized that Gly482Ser mutation impairs the abilities of PGC-1 in ameliorating overnutrition-induced hepatocyte fat deposition and in stimulating hepatocyte expression of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by a key PGC-1 target gene). In the present study, treatment of cultured hepatocytes with palmitate induced fat deposition, serving as a cell model of hepatic steatosis. Upon overexpression of wild-type PGC-1, H4IIE cells exhibited a significant decrease in palmitate-induced hepatocyte fat deposition compared with control cells and/or cells upon overexpression of mutant PGC-1 (Gly482Ser). Overexpression of wild-type PGC-1, but not mutant PGC-1, also caused a significant increase in hepatocyte expression of carnitine palmitoyl transferase 1a, a rate-determining enzyme that transfers long-chain fatty acids into mitochondria for oxidation. In addition, overexpression of mutant PGC-1 did not stimulate PEPCK-C expression as overexpression of wild-type PGC-1 did, likely due to a decrease in the ability of mutant PGC-1 in increasing PEPCK promoter transcription activity. Together, these results suggest that Gly482Ser mutation impairs the abilities of PGC-1 in decreasing fat deposition and in stimulating PEPCK-C expression in cultured hepatocytes.
