Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption

Abstract

BackgroundDiet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates.ResultsWe conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16–18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis.ConclusionA subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1439-8) contains supplementary material, which is available to authorized users.

Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes

“…Far fewer associations were found to be significant (49 out of 230 tests, ≈ 21%). We observed the same pattern of associations between the prioritised lipid species and known CMS risk factors using data from the present study ( Fig.3D; Table S27), as well as in a biopsy-confirmed non-alcoholic steatohepatitis (NASH) cohort comprising 73 individuals (Sanders et al, 2018) (Fig.S4; Table S27).…”

A high-throughput platform for detailed lipidomic analysis of a range of mouse and human tissues

“…This analysis also uncovers the pattern that odd-chain fatty acid residues are more abundant in the hearts of lean mice. These results are interpretable in terms of the aetiology of metabolic and heart disease [24,[41][42][43][44] in a manner that is orthogonal to the abundance analysis of whole lipids.…”

Revealing grand-paternal programming of lipid metabolism using a novel computational tool

“…This led us to test the hypothesis that a higher carbohydrate diet consumed by fathers altered de novo lipogenesis (DNL) in offspring. We elected to use a targeted approach for testing this, using known markers of de novo lipogenesis (DNL) 22 and reference variables not associated with DNL. The abundance of all DNL TGs was typically much higher in CNS tissue in the LP-HC group (Extended data Fig.…”

“…This was designed to increase de novo lipogenesis; a high-fat diet would be less useful as it would alter lipid intake as well as biosynthesis. Although the programming effects on lipogenesis were expected to be focused on the offsprings' liver, the products of lipid biosynthesis are typically distributed throughout the organism quickly, especially triglycerides (TG) 22 . Testing this hypothesis therefore also required a tool for analysing systemic lipid metabolism and distribution.…”