Abstract
The role of hepaticde novolipogenesis (DNL) in promoting fatty liver disease and hypertriglyceridemia during excessive nutrient intake is becoming firmly established. Certain nutrients such as fructose promote hepatic DNL activity and this has been at least partly attributed to their efficient conversion to the acetyl-CoA precursors of DNL. However, tracer studies indicate a paradoxically low level of fructose incorporation into lipids, which begs the question of what the actual lipogenic acetyl-CoA sources are under these and other conditions. Here, we describe novel approaches for measuring substrate contributions to lipogenic hepatic acetyl-CoA using13C-tracers and13C-NMR analysis of lipids and acetyl-CoA probes. We review and address aspects of hepatic intermediary fluxes and acetyl-CoA compartmentation that can confound the relationship between13C-precursor substrate and lipogenic13C-acetyl-CoA enrichments and demonstrate novel methodologies that can provide realistic estimates of13C-enriched substrate contributions to DNL. The most striking realization is that the principal substrate contributors to lipogenic acetyl-CoA have yet to be identified, but they are probably not the so-called “lipogenic substrates” such as fructose. The proposed methods may improve our insight into the nutrient sources of DNL under various feeding and disease states.
Highlights
OverviewDe novo lipogenesis (DNL) is a constitutive pathway that transforms acetyl-CoA into long-chain fatty acids
The role of hepatic de novo lipogenesis (DNL) in promoting fatty liver disease and hypertriglyceridemia during excessive nutrient intake is becoming firmly established
We review and address aspects of hepatic intermediary fluxes and acetyl-CoA compartmentation that can confound the relationship between 13C-precursor substrate and lipogenic 13C-acetyl-CoA enrichments and demonstrate novel methodologies that can provide realistic estimates of 13C-enriched substrate contributions to DNL
Summary
De novo lipogenesis (DNL) is a constitutive pathway that transforms acetyl-CoA into long-chain fatty acids. The liver is a principal site for DNL and, as previously mentioned, hepatic intermediary metabolism is characterized by extensive cycling of pyruvate and Krebs cycle intermediates, which causes extensive randomization of 13C derived from glycolytic sources such as glucose and fructose. This results in the generation of multiple acetyl-CoA isotopomers from substrates such as [113C]glucose that in the absence of pyruvate cycling would generate one specific acetyl-CoA isotopomer (in this case [213C]acetyl-CoA). The randomization of pyruvate limits the resolution of acetyl-CoA 13Cisotopomers from glycolytic 13C-enriched substrates but can provide novel and important information on the contributions of important glycolytic sources such as fructose and glucose to the lipogenic acetyl-CoA pool [7]
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