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

Antwi‐Boasiako Oteng,Anke Loregger,Noam Zelcer,Sander Kersten,Michel Van Weeghel

doi:10.1002/mnfr.201900385

Abstract

ScopeThe 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 resultsHepa1‐6 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.ConclusionElaidate 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.

Highlights

Trans fatty acids are unsaturated fatty acids with at least one double bond in the trans configuration
To better characterize the molecular pathways activated by industrial trans fatty acids in liver and fat cells, we determined the effects of elaidate on whole genome gene expression in mouse hepatoma Hepa1-6 cells and mouse 3T3-L1 adipocytes
We find that feeding mice a diet enriched in industrial trans fatty acids enhances liver steatosis and fibrosis, and raises hepatic triglyceride levels, hepatic cholesterol levels, and plasma ALT activity in comparison with diets enriched in cis-unsaturated or saturated fatty acids. 2) in vitro, the industrial trans fatty acid elaidate, but not ruminant trans fatty acids, stimulates the cholesterol synthesis pathway in liver cells via activation of the sterol regulatory element binding proteins (SREBPs) cleavage–activating protein (SCAP)–sterol regulatory element-binding protein 2 (SREBP2) axis, presumably by lowering intracellular free cholesterol and desensitizing SCAP to cholesterol

Summary

Introduction

Trans fatty acids are unsaturated fatty acids with at least one double bond in the trans configuration. Part of the trans fatty acids consumed by humans are industrially produced by partial hydrogenation of vegetable oils and are present in deep fried foods, pastries, cookies, margarine, and popcorns. The other set of trans fatty acids are synthesized naturally in the gut of ruminants by bacterial biohydrogenation and are present in meat and dairy products of cattle, goat, and sheep.[3–5]. Hydrogenated vegetable oils and trans fatty acids are used by the food industry because they confer a combination of beneficial properties to food products, including a long shelf life and a pleasant mouthfeel. In response to growing evidence linking intake of trans fatty acids to coronary heart disease, most food manufacturers and retailers have largely removed trans fatty acids

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