Hepatic lipogenesisAs mentioned abo

Hepatic lipogenesis
As mentioned above, hepatic FAs either derive from endogenous
lipogenesis, are released from lysosomes by autophagy, or derive
from the free FA (FFA) plasma pool via active uptake into the
hepatocyte. Depending on the metabolic state, FAs are then either
processed to TAGs and stored or rapidly metabolized. Indeed,
b-oxidation is the predominant source of energy during the fasting
state.
Hepatic lipogenesis includes de novo synthesis of FAs from
acetyl-CoA or malonyl-CoA and further processing to TAGs. In
mammals, FA synthesis is catalyzed by acetyl-CoA carboxylase
(ACC) and fatty acid synthase (FAS) – an enzyme that is complexly
regulated by various nuclear receptors (PPARa, PPARc
and the bile acid receptor/farnesoid X receptor [FXR]) [18–20].
FA elongation requires NADPH as a reducing reagent, which is
provided by the pentose phosphate pathway (Fig. 2B). Remarkably,
PPARa itself is activated by a phospholipid synthesized by
FAS, indicating a feedback loop [21].
A close link between glucose and lipid metabolism is indicated
by the fact that nuclear receptors (NRs) are also important
mediators of insulin signaling and since DNL occurs under anabolic
condition. The existence of such a link is further supported
by the fact that insulin stimulates FAS expression via the phosphoinositide-
3-kinase (PI3K) pathway [22]. On a transcriptional
level, SREBP-1c and carbohydrate-responsive element binding
protein (ChREBP), a glucose dependant transcription factor, synergistically
induce expression of FAS and ACC [23].
As FAs and their metabolites are the major cause for lipotoxicity
and promote the formation of ROS, FAs are stored for future
use as TAGs, which are relatively inert and consist of three FAs
esterified to a glycerol backbone. TAGs are then either stored in
lipid 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 VLDL
particles, by conjugation to apoB-100 in a 5:1 TAG/cholesterol