Effect of diet on expression of genes involved in lipid metabolism, oxidative stress, and inflammation in mouse liver-insights into mechanisms of hepatic steatosis

PLoS One. 2014 Feb 14;9(2):e88584. doi: 10.1371/journal.pone.0088584. eCollection 2014.

Abstract

Nutritional intake is a fundamental determinant of health. Many studies have correlated excess caloric intake, as well as a high ratio of n-6:n-3 fatty acids, with detrimental health outcomes, such as the metabolic syndrome. In contrast, low-calorie diets have beneficial health effects. Despite these associations, our understanding of the causal relationship between diet and health remains largely elusive. The present study examined the molecular changes elicited by nine diets with varying fat, sugar, cholesterol, omega-3 fatty acids, omega-6 fatty acids, and calories in C57BL/6 male mice. Microarray analyses were conducted on liver samples from three mice per diet and detected 20,449 genes of which 3,734 were responsive to changes in dietary components. Principal component analysis showed that diet restriction correlated the least with the other diets and also affected more genes than any other diet. Interestingly, Gene Set Enrichment Analysis (GSEA) identified gene sets involved in glutathione metabolism, immune response, fatty acid metabolism, cholesterol metabolism, ABC transporters, and oxidative phosphorylation as being highly responsive to changes in diet composition. On the gene level, this study reveals novel findings such as the induction of the drug efflux pump Abcb1a (p-glycoprotein) by diet restriction and an atherogenic diet, as well as the suppression of the rate limiting step of bile acid synthesis, Cyp7a1, by a high fructose diet. This study provides considerable insight into the molecular changes incurred by a variety of diets and furthers our understanding of the causal relationships between diet and health.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Biosynthetic Pathways / genetics
  • Cholesterol / biosynthesis
  • Cluster Analysis
  • Diet*
  • Fatty Acids / biosynthesis
  • Fatty Liver / complications
  • Fatty Liver / genetics*
  • Fatty Liver / pathology
  • Gene Expression Regulation*
  • Homeostasis / genetics
  • Inflammation / complications
  • Inflammation / genetics*
  • Lipid Metabolism / genetics*
  • Liver / metabolism
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / genetics*
  • Principal Component Analysis
  • Signal Transduction / genetics
  • Software
  • Transcriptome / genetics

Substances

  • ATP-Binding Cassette Transporters
  • Fatty Acids
  • Cholesterol

Grant support

This work was supported by NIH grant ES009649. Helen J Renaud is supported by a Canadian Institutes of Health Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.