%0 Journal Article
%T Identifying Sources of Hepatic Lipogenic Acetyl-CoA Using Stable Isotope Tracers and NMR
%A John G. Jones
%J Advances in Radiology
%D 2014
%R 10.1155/2014/109252
%X The role of hepatic de novo lipogenesis (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 using 13C-tracers and 13C-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 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. 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 ˇ°lipogenic substratesˇ± such as fructose. The proposed methods may improve our insight into the nutrient sources of DNL under various feeding and disease states. 1. Overview De novo lipogenesis (DNL) is a constitutive pathway that transforms acetyl-CoA into long-chain fatty acids. In humans, DNL occurs primarily in the liver, [1] while, in rodents and other mammals, adipose tissue can also be important contributors [2, 3]. A widely accepted teleological function of this pathway is the conversion of excess nutrient carbons into an inert and energy-dense triglyceride product that can be stored and mobilized at a later time for energy generation in times of nutrient scarcity. DNL activity is highly regulated both allosterically and transcriptionally such that it normally only operates during conditions of nutrient and energy satiety. For the liver, this represents the absorptive and early postabsorptive feeding phase where there are high portal vein levels of simple sugars and amino acids coupled with increased amounts of insulin. The loss of regulation of hepatic DNL flux secondary to excess nutrient consumption may be an important early event in the development of fatty liver and hypertriglyceridemia, which in turn are harbingers of diabetes and liver disease. Given the steep parallel increases in obesity rates and nonalcoholic fatty liver disease in most
%U http://www.hindawi.com/journals/ara/2014/109252/