Industrial Trans Fatty Acids Stimulate SREBP2-Mediated Cholesterogenesis and Promote Non-Alcoholic Fatty Liver Disease

Mol Nutr Food Res. 2019 Oct;63(19):e1900385. doi: 10.1002/mnfr.201900385. Epub 2019 Aug 7.


Scope: The mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non-alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids.

Methods and results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated, or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element-binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage-activating protein (SCAP), yet independent of liver-X receptor and ubiquitin regulatory X domain-containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets.

Conclusion: Elaidate induces cholesterogenesis in vitro by activating the SCAP-SREBP2 axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

Keywords: cholesterogenesis; cholesterol metabolism; elaidate; non-alcoholic fatty liver disease; sterol regulatory element binding proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • CHO Cells
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cholesterol / biosynthesis*
  • Cholesterol / genetics
  • Cricetulus
  • Dietary Fats / pharmacology*
  • Gene Expression / drug effects
  • Intracellular Signaling Peptides and Proteins / physiology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / chemically induced*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Oleic Acids / pharmacology
  • Sterol Regulatory Element Binding Protein 2 / physiology*
  • Trans Fatty Acids / pharmacology*


  • Dietary Fats
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oleic Acids
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 2
  • Trans Fatty Acids
  • elaidic acid
  • Cholesterol