The obesogenic effects of polyunsaturated fatty acids are dependent ...

high dietary PUFAs, the modulation is less clear. PUFAs have been shown to suppress hepatic
Srebp-1c transcription 53 , mRNA stability 54 and its proteolytic activation 55 through liver X receptor
(LXR) 56 - and/or SREBP-1c 55 - mediated pathways. In our study, the suppression on Srebp-1c
transcription was only sustained when diets were supplemented with protein but abolished when
combined with sucrose (Fig1.3B, 2.7A). The most straight forward explanation would be that
increased insulin levels played a role, as multiple lines of evidence suggested the importance of
insulin in controlling expression and activity of Srebp-1c 57 . But further in our study it was
elucidated otherwise, as modulating insulin secretion by pharmaceutical drugs did not have any
effect on either Srebp-1c mRNA abundance or its activity, judged by the transcription of its target
genes Scd1, Fasn and Acaca (Fig2.5E 2.7A).
The role of glucose in the context of this story needs also to be discussed. Besides insulin,
carbohydrate ingestion can very efficiently lead to the induction of lipogenic genes 58 . However,the
main sensor of glucose carbohydrate-responsive element–binding protein (ChREBP) 59 , like
SREBP-1c, was also suppressed in the presence of PUFAs 60 . Mitro et al. has shown that LXRs
could also work as glucose sensors to regulate cholesterol metabolism genes and in some degree
lipogenic genes as well 61 . In the LXRα/β knockout model, high carbohydrate diet-induced hepatic
gene expression of Scd1 and Fasn were attenuated 62 . As a whole, they suggest that in response to
glucose stimuli, LXR-dependent pathway is indispensable for the full activation of Scd1 and Fasn
expression, while the regulation of Acaca is mostly under the control of ChREBP 60 . So in our high
fish oil feeding supplemented with different starches, the observed elevation of Scd1 and Fasn
expression with high GI diet (Fig2.4G) could be explained as under the impact of fish oil, only LXR
was still able to sense plasma glucose changes though mechanism that is still under debate 63,64 . Of
course all speculations need supporting evidence from follow up studies. And with mTORC1 65,66
and AMP-activated protein kinase (AMPK) 67,68 also in the picture now, the already intricate control
of SREBP-1c and lipogenesis is only going to be more complicated.
Fructose
The increased world consumption of fructose or high-fructose corn syrup has been associated with
the obesity epidemic 69,70 . Fructose is taken up by the liver rapidly because of the low Km of
fructokinase towards fructose 71 . Without the negative feedback on phosphofructokinase as in
glucose metabolism, the reactions continue to provide substrate for glucose and lipid production 71 .
13