Transcription profiling in the liver of undernourished male rat offspring reveals altered lipid metabolism pathways and predisposition to hepatic steatosis.

Abstract

Clinical and animal studies have reported an association between low birth weight and the development of non-alcoholic fatty liver disease (NAFLD) in offspring. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we previously showed that maternal undernutrition predisposes offspring to altered lipid metabolism in adipose tissue, especially under high-fat (HF) diet. Here, using microarray-based expression profiling combined with metabolic, endocrine, biochemical, histological and lipidomic approaches, we assessed whether FR30 procedure sensitizes adult male offspring to impaired lipid metabolism in the liver. No obvious differences were noted in the concentrations of triglycerides, cholesterol and bile acids in the liver of 4-month-old FR30 rats whatever the post-weaning diet used. However, several clues suggest that offspring s lipid metabolism and steatosis are modified by maternal undernutrition. First, lipid composition was changed (i.e., higher total saturated fatty acids and lower elaidic acid) in the liver whereas larger triglyceride droplets were observed in hepatocytes of undernourished rats. Second, FR30 offspring exhibited long-term impact on hepatic gene expression and lipid metabolism pathways under chow diet. Although the transcriptome profile was globally modified by maternal undernutrition, cholesterol and bile acids biosynthesis pathways appear as key targets indicating that FR30 animals were predisposed to impaired hepatic cholesterol metabolism. Third, FR30 procedure markedly modifies hepatic gene transcription profiles in undernourished offspring in response to post-weaning HF. Overall, FR30 offspring may exhibit impaired metabolic flexibility which does not enable them to properly cope with post-weaning nutritional challenges influencing the development of non-alcoholic fatty liver (NAFL).