Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 244

activity, and selectively inducing the IRE1-JNK pathway (Kato et al., 2011).
These observations highlight the delicate balance that exists between cel-
lular energy sensing and ER stress.
5.2. UPR Regulation of Lipid Metabolism
ER stress is known to stimulate lipogenesis through the UPR, thus providing
lipids for ER expansion, a hallmark of cellular adaptation. ER stress activates,
for example, SREBP1 ( Wang et al., 2005 ), as well as SREBP2 ( Colgan et al.,
2007 ), two master transcriptional regulators of fatty acid and cholesterol
biosynthesis. Relief of ER stress by overexpression of BiP/GRP78 inhibits
SREBP1 activation in the liver of ob/ob mice, highlighting the importance
of the UPR in the control of lipid metabolism ( Kammoun et al., 2009 ).
As mentioned in previous sections, the IRE1/XBP1 pathway was first
shown to be important for the differentiation of highly secretory cells, such
as antibody-secreting B cells. Likewise, XBP1-deficient cells are report-
edly deficient in adipogenic differentiation ( Sha et al., 2009 ). XBP1 was
shown to be directly downstream the essential adipogenic factor C/EBPβ,
and splicing of this factor is indispensible for the development of the adi-
pose phenotype. One mechanism by which XBP1 promotes lipogenesis is
through activation of enzymes of the CDP-choline pathway, thus leading
to increased phosphatidylcholine biosynthesis and ER biogenesis ( Sriburi
et al., 2004 , 2007 ). In the liver, the IRE1/XBP1 pathway directly controls
genes involved in fatty acid synthesis in response to carbohydrate diet, while
hepatic deletion of XBP1 causes hypocholesterolemia and hypotriglyceri-
demia ( Lee et al., 2008 ). Furthermore, hepatocyte-specific IRE1 deletion
predisposes mice to ER stress-induced hepatosteatosis, suggesting that this
UPR sensor is also important for intracellular lipid secretion and accumula-
tion ( Zhang et al., 2011 ).
PERK has also been demonstrated to be important for lipogenic tissue
development since knockout mice have impaired mammary gland lipogen-
esis during pregnancy, which results in reduced free fatty acid content of the
milk ( Bobrovnikova-Marjon et al., 2008 ). Loss of PERK also resulted in a
decrease in key lipogenic enzymes, such as stearyl-CoA desaturase-1, fatty
acid synthase and ATP citrate lyase, due to excessive activation of SREBP1,
the master regulator of lipid homeostasis within the cell. The PERK path-
way is also important for development of hepatosteatosis in mice fed a high-
fat diet. Reduction of eIF2α phosphorylation results in a lower expression
of PPARγ and C/EBP, key transcriptional regulators of lipid synthesis
( Oyadomari et al., 2008 ).