Abstract
BackgroundThe purpose of this study was to investigate the effects of sub-chronic high fat, high sucrose diet (also termed ‘Westernized diet’ or WD) feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development.MethodsBrown Norway male rats (9 months of age) were randomly assigned to receive ad libitum access to a control (CTL; 14 % kcal fat, 1.2 % sucrose by weight) diet or WD (42 % kcal from fat, 34 % sucrose by weight) for 6 weeks.ResultsSix weeks of WD feeding caused hepatic steatosis development as evidenced by the 2.25-fold increase in liver triacylglycerol content, but did not induce advanced liver disease (i.e., no overt inflammation or fibrosis) in adult Brown Norway rats. RNA deep sequencing (RNA-seq) revealed that 94 transcripts were altered in liver by WD feeding (46 up-, 48 down-regulated, FDR < 0.05). Specifically, the top differentially regulated gene network by WD feeding was ‘Lipid metabolism, small molecular biochemistry, vitamin and mineral metabolism’ (Ingenuity Pathway Analysis (IPA) score 61). The top-regulated canonical signaling pathway in WD-fed rats was the ‘Superpathway of cholesterol biosynthesis’ (10/29 genes regulated, p = 1.68E-17), which coincides with a tendency for serum cholesterol levels to increase in WD-fed rats (p = 0.09). Remarkably, liver stearoyl-CoA desaturase (Scd) mRNA expression was by far the most highly-induced transcript in WD-fed rats (approximately 30-fold, FDR = 0.01) which supports previous literature underscoring this gene as a crucial target during NAFLD development.ConclusionsIn summary, sub-chronic WD feeding appears to increase hepatic steatosis development over a 6-week period but only induces select inflammation-related liver transcripts, mostly acute phase response genes. These findings continue to outline the early stages of NAFLD development prior to overt liver inflammation and advanced liver disease.
Highlights
The purpose of this study was to investigate the effects of sub-chronic high fat, high sucrose diet feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development
While it has demonstrated that longer high-fat/ high-sugar feeding schedules cause increases in liver inflammation [17], oxidative stress [18], fibrosis [17, 18] and mitochondrial dysfunction [19, 20], we here provide evidence that sub-chronic Western diet (WD) feeding causes a rapid dysregulation in select hepatic lipid and cholesterol metabolism genes in rats; an effect which: a) may contribute to the doubling in hepatic TG content presented ; and b) may be responsible for serum cholesterol levels tending to increase after 6 weeks of WD feeding as previously reported [10]
Notwithstanding, we contend that the marked dysregulation in hepatic lipid metabolism and cholesterol biosynthesis genes after 6 weeks of WD feeding is reflective of the phenotypic changes we report at the tissue level
Summary
The purpose of this study was to investigate the effects of sub-chronic high fat, high sucrose diet ( termed ‘Westernized diet’ or WD) feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development. NAFLD is a progressive liver disease ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis [3]. It is characterized by elevated hepatic triglyceride (TG) storage (≥5 % by weight) in the absence of excessive alcohol consumption (
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