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

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...

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Vydáno v:	Molecular nutrition & food research Ročník 63; číslo 19; s. e1900385 - n/a
Hlavní autoři:	Oteng, Antwi‐Boasiako, Loregger, Anke, Weeghel, Michel, Zelcer, Noam, Kersten, Sander
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Germany Wiley Subscription Services, Inc 01.10.2019 John Wiley and Sons Inc
Témata:	3T3-L1 Cells Alanine Alanine transaminase Animals Biosynthesis Body fat Carcinoma, Hepatocellular Cell Line, Tumor CHO Cells cholesterogenesis Cholesterol Cholesterol - biosynthesis Cholesterol - genetics cholesterol metabolism Cricetulus Diet Dietary Fats - pharmacology elaidate enzyme activity Fatty acids Fatty liver Fibrosis Gene expression Gene Expression - drug effects gonads Hepatoma Intracellular Intracellular Signaling Peptides and Proteins - physiology Liver Liver - drug effects Liver - metabolism Liver - pathology Liver diseases Liver X receptors Male mechanism of action Membrane Proteins - physiology Mice Mice, Inbred C57BL Molecular modelling Non-alcoholic Fatty Liver Disease - chemically induced Non-alcoholic Fatty Liver Disease - metabolism Non-alcoholic Fatty Liver Disease - pathology non‐alcoholic fatty liver disease oleic acid Oleic Acids - pharmacology palmitates Palmitic acid Proteins saturated fatty acids Steatosis Sterol Regulatory Element Binding Protein 2 - physiology sterol regulatory element binding proteins Sterol regulatory element-binding protein Trans fats Trans fatty acids Trans Fatty Acids - pharmacology transcriptomics Ubiquitin elaidate non-alcoholic fatty liver disease sterol regulatory element binding proteins cholesterol metabolism cholesterogenesis
ISSN:	1613-4125, 1613-4133, 1613-4133
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Shrnutí:	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. The cholesterogenic effect of the trans fatty acid elaidate is due in part to its ability to reduce levels of intracellular cholesterol, and reduce the sensitivity of sterol regulatory element binding protein (SREBP) cleavage–activating protein (SCAP) to cholesterol. These properties result in the activation of the SREBP signaling pathway, leading to increased expression of genes involved in cholesterol biosynthesis.
Bibliografie:	The copyright line for this article was changed on 11 September 2019 after original online publication. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1613-4125 1613-4133 1613-4133
DOI:	10.1002/mnfr.201900385