Hepatic lipogenesisAs mentioned above, hepatic FAs either derive from endogenouslipogenesis, are released from lysosomes by autophagy, or derivefrom the free FA (FFA) plasma pool via active uptake into thehepatocyte. Depending on the metabolic state, FAs are then eitherprocessed to TAGs and stored or rapidly metabolized. Indeed,b-oxidation is the predominant source of energy during the fastingstate.Hepatic lipogenesis includes de novo synthesis of FAs fromacetyl-CoA or malonyl-CoA and further processing to TAGs. Inmammals, FA synthesis is catalyzed by acetyl-CoA carboxylase(ACC) and fatty acid synthase (FAS) – an enzyme that is complexlyregulated by various nuclear receptors (PPARa, PPARcand the bile acid receptor/farnesoid X receptor [FXR]) [18–20].FA elongation requires NADPH as a reducing reagent, which isprovided by the pentose phosphate pathway (Fig. 2B). Remarkably,PPARa itself is activated by a phospholipid synthesized byFAS, indicating a feedback loop [21].A close link between glucose and lipid metabolism is indicatedby the fact that nuclear receptors (NRs) are also importantmediators of insulin signaling and since DNL occurs under anaboliccondition. The existence of such a link is further supportedby the fact that insulin stimulates FAS expression via the phosphoinositide-3-kinase (PI3K) pathway [22]. On a transcriptionallevel, SREBP-1c and carbohydrate-responsive element bindingprotein (ChREBP), a glucose dependant transcription factor, synergisticallyinduce expression of FAS and ACC [23].As FAs and their metabolites are the major cause for lipotoxicityand promote the formation of ROS, FAs are stored for futureuse as TAGs, which are relatively inert and consist of three FAsesterified to a glycerol backbone. TAGs are then either stored inlipid droplets within the hepatocyte or processed to VLDL [7].TAG synthesis is catalyzed by the enzymes mitochondrial glycerol-3-phosphate-acyltransferase (mtGPAT) and diacylglycerolacyltransferase(DGAT) [24]. TAGs are then packaged into VLDLparticles, by conjugation to apoB-100 in a 5:1 TAG/cholesterol
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