Abstract:
Previously we reported that a high fat, high sugar (HFHS) diet induced adiposity, hyperinsulinaemia, hyperleptinaemia,
hypertriglyceridaemia and increased liver mass in male Wistar rats. In the present study, the
mechanisms underlying the increased liver mass were further elucidated by assessing hepatic lipid accumulation
and the expression and methylation status of key metabolic genes using histology, quantitative real-time PCR and
pyrosequencing, respectively. The HFHS diet induced hepatic steatosis, increased hepatic triglycerides (1.8-fold,
p < 0.001), and increased the expression of sterol regulatory element-binding transcription factor 1 (Srebf1) (2.0-
fold, p < 0.001) and peroxisome proliferator-activated receptor gamma (Pparg) (1.7-fold, p = 0.017) in the liver.
The expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1a) was decreased
(2.6-fold, p < 0.010), which was accompanied by hypermethylation (p = 0.018) of a conserved CpG site in the
promoter of Pgc1a in HFHS fed rats compared to controls. In silico analysis identified putative binding sites for
CCAAT/enhancer-binding protein beta (C/EBPß) and hepatocyte nuclear factor 1 (HNF1) within proximity to the
hypermethylated CpG. As Pgc1a is a co-activator of several transcription factors regulating multiple metabolic
pathways, hypermethylation of this conserved CpG site in the promoter of Pgc1a may be one possible mechanism
contributing to the development of hepatic steatosis in response to a HFHS diet. However, further work is
required to confirm the role of Pgc1a in steatosis.
