Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 245

On the other hand, ATF6 has also been implicated in lipid metabolism.
ATF6 knockout mice treated with tunicamycin develop hepatosteatosis to
a higher degree than wild-type mice. In these animals, a more pronounced
decrease in the expression of genes related to lipid handling, such as PGC1α,
PPARα and SREBP1, is observed, which results in increased lipid accumu-
lation in the liver. However, unlike the other UPR pathways, ATF6 seems
to be more important for fatty acid oxidation than lipid biosynthesis ( Rut-
kowski et al., 2008 ).
5.3. UPR Regulation of Carbohydrate Homeostasis
In rat liver, it was recently shown that physiological postprandial increases in
glucose and lipids cause ER stress ( Boden et al., 2011 ), suggesting that the
UPR may participate in carbohydrate metabolism. FOXO1, a transcription
factor that promotes hepatic gluconeogenesis and inhibits glucose utilization
( Zhang et al., 2006 ), is regulated by XBP1 in an ER stress response-inde-
pendent manner ( Zhou et al., 2011 ). Spliced XBP1 interacts with FOXO1
to enhance proteasome-mediated degradation. This effect is observed even
at low levels of XBP1 that are unable to induce UPR-related genes. This
evidence shows that UPR sensors control carbohydrate metabolism and
diminish glucose production. Alternatively, another line of evidence links
ER stress-induced JNK hyperactivation to increased FOXO1 activity and
increased hepatic gluconeogenesis ( Lim et al., 2009 ). This mechanism may
be important for regulation of blood sugar during long periods of hypogly-
cemia since this condition has been shown to induce ER stress in the liver,
thereby linking the UPR and glucose production ( Gonzales et al., 2008 ).
These contradictory results suggest that the connection between UPR and
hepatic glucose handling is complex and further studies are required to fully
dissect the details.
The pathological implications of UPR for glucose metabolism in dif-
ferent organs have been extensively documented in recent years, due to its
importance in understanding type 2 diabetes. This issue will be covered in
the next section.
5.4. ER Stress-Modulated Mitochondrial Metabolism
While the role of the ER as a physiologically relevant calcium store is well
established, a similar role for mitochondria has been long debated. Cal-
cium ions are known to be taken up by mitochondria and to accumulate
in the mitochondrial matrix ( Deluca and Engstrom, 1961 ; Vasington and
Murphy, 1962 ), but the relevance of this process remained unclear. Moreover,