High Fat Feeding Induces Hepatic Fatty Acid Elongation in Mice

Maaike H Oosterveer,Theo H Van Dijk,Folkert Kuipers,Uwe J F Tietge,Rick Havinga,Albert K Groen,Frans Stellaard,Theo Boer,Dirk-Jan Reijngoud

doi:10.1371/journal.pone.0006066

Abstract

BackgroundHigh-fat diets promote hepatic lipid accumulation. Paradoxically, these diets also induce lipogenic gene expression in rodent liver. Whether high expression of these genes actually results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated.Methodology/Principal FindingsTo interrogate this apparent paradox, we have quantified de novo lipogenesis in C57Bl/6J mice fed either chow, a high-fat or a n-3 polyunsaturated fatty acid (PUFA)-enriched high-fat diet. A novel approach based on mass isotopomer distribution analysis (MIDA) following 1-13C acetate infusion was applied to simultaneously determine de novo lipogenesis, fatty acid elongation as well as cholesterol synthesis. Furthermore, we measured very low density lipoprotein-triglyceride (VLDL-TG) production rates. High-fat feeding promoted hepatic lipid accumulation and induced the expression of lipogenic and cholesterogenic genes compared to chow-fed mice: induction of gene expression was found to translate into increased oleate synthesis. Interestingly, this higher lipogenic flux (+74 µg/g/h for oleic acid) in mice fed the high-fat diet was mainly due to an increased hepatic elongation of unlabeled palmitate (+66 µg/g/h) rather than to elongation of de novo synthesized palmitate. In addition, fractional cholesterol synthesis was increased, i.e. 5.8±0.4% vs. 8.1±0.6% for control and high fat-fed animals, respectively. Hepatic VLDL-TG production was not affected by high-fat feeding. Partial replacement of saturated fat by fish oil completely reversed the lipogenic effects of high-fat feeding: hepatic lipogenic and cholesterogenic gene expression levels as well as fatty acid and cholesterol synthesis rates were normalized.Conclusions/SignificanceHigh-fat feeding induces hepatic fatty acid synthesis in mice, by chain elongation and subsequent desaturation rather than de novo synthesis, while VLDL-TG output remains unaffected. Suppression of lipogenic fluxes by fish oil prevents from high fat diet-induced hepatic steatosis in mice.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is one of the hallmarks of the metabolic syndrome and is strongly associated with obesity and insulin resistance [1]
Expression of genes encoding enzymes involved in hepatic fatty acid (Acc, fatty acid synthase (Fas), stearoyl-CoA desaturase 1 (Scd1), Elovl6) and TG synthesis (Dgat, glycerol-3-phosphate acyltransferase (Gpat)) was induced in mice fed the high-fat diet compared to animals receiving chow
The major finding of our study is that the counterintuitive induction of hepatic lipogenic genes upon high-fat feeding is paralleled by adaptive remodelling of hepatic fatty acids rather than to increased de novo lipogenesis

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is one of the hallmarks of the metabolic syndrome and is strongly associated with obesity and insulin resistance [1]. High-fat feeding has been reported to result in a paradoxical increase in the expression of lipogenic genes in mouse liver. An inhibition of the activity of lipogenic transcription factors and the subsequent suppression of their target genes by n-3 PUFA [12] is considered to contribute to the protective effects of fish oil. These observations suggest that the activity of lipogenic enzymes is related to the degree of high fat diet-induced hepatic steatosis, an increased de novo fatty acid synthesis appears counterintuitive under conditions of a high dietary fatty acid load. Whether high expression of these genes results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated

Methods

Results

Conclusion