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

Abstract

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.

Physicochemical Properties and Effects of Honeys on Key Biomarkers of Oxidative Stress and Cholesterol Homeostasis in HepG2 Cells

“…It also upregulated SREBP2 downstream genes, HMGCR and LDLR, at 1.0% but not at 2.0% (3.9- and 1.2-fold change relative to control, respectively). This finding is consistent with an increased TC content ( Figure 5 A) and is in line with previous studies [ 64 , 65 ], suggesting that 1.0% analogue stimulates the cholesterol synthesis in the fatty acid-induced HepG2 cells, likely through the SCAP-SREBP2 pathway by lowering free cholesterol in the cells and/or desensitizing SCAP to cholesterol [ 64 ]. The 1% analogue also upregulates the LXRα and PPARα ( Figure 6 A).…”

“…However, it is evidenced that cholesterol exits as free cholesterol and cholesteryl esters in hepatocytes [ 75 ]. In the current investigation, although jiaogulan and olive honeys did not lead to a decrease in TC content after 24 h ( Figure 5 E,F), they possibly induced a conversion of free cholesterol to cholesteryl esters through the esterification of cholesterol with fatty acids to protect the cells from free cholesterol toxicity, while modulating the tested genes in the pattern of AMPK-SREBP2 pathway, responsive to a reduction in cellular free cholesterol content [ 64 ].…”

“…Jaogulan and olive modulated the tested gene in the pattern that should lead to a TC reduction, but this reduction did not occur ( Figure 5 E,F). They possibly protected the cells from increased cholesterol accumulation that we recorded through stimulating the conversion of free cholesterol to cholesteryl esters, while they modulated the tested genes in the pattern of AMPK-SREBP2 pathway to reduce cellular free cholesterol content [ 64 ]. Although the tested honeys (except olive honey) activated PPARα , all of them did not reduce cellular triglyceride content in fatty acid-induced HepG2 cells.…”

Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View

“…Diet has a relevant role in the development and progression of NAFLD, since a high energy intake and consumption of specific nutrients have a direct impact on the abnormal accumulation of TG in the liver, a hallmark of NAFLD [4]. High intake of nutrients that include saturated fatty acids (FA) such as palmitic acid (C16:0) [17][18][19] and trans FA of industrial origin [20] decrease FA oxidation (FAO), stimulate the synthesis and secretion of TGs, and trigger lipotoxic effects in the liver [4,17,18]. Moreover, high intake of n-6 PUFA, especially linoleic acid (C18:2n-6), and low consumption of n-3 LCPUFA (EPA and DHA) also appear to favor the development of hepatic steatosis [21].…”

Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease

“…Development and progression of NAFLD are associated with a high energy intake and consumption of specific nutrients such as saturated fatty acids (FAs) (i.e., palmitate) [ 151 ], trans FAs [ 152 ] and carbohydrates (i.e., glucose, fructose) [ 153 ]. Besides, derangement in the intake of n-6 long-chain polyunsaturated FAs (n-6 LCPUFAs) and n-3 LCPUFAs enhancing the n-6/n-3 LCPUFA ratio [ 154 ] also occur, promoting the abnormal deposition of triglycerides (TGs) in the liver.…”