Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 248

pathologies are also characterized by a marked decrease in cellular metabo-
lism; however, the molecular mechanisms responsible for this dysfunction
are not fully understood. As discussed previously, alterations in the contacts
between ER and mitochondria, and more importantly, in calcium transfer
between these two organelles, could lead to mitochondrial dysfunction and
the metabolic imbalance observed in these diseases ( Fig. 5.5 ). Moreover,
recent studies have also linked ER-mitochondria communication to can-
cer growth and progression. The influence of both organelle interplay and
UPR signaling on human pathologies will be discussed subsequently.
6.1. UPR and Diabetes
Diabetes mellitus (DM) is considered a multifactorial pathology and is asso-
ciated with obesity, dyslipidemia, endothelial dysfunction, inflammation and
hypertension ( Petersen and Shulman, 2006 ). T2DM is one of the most com-
mon diseases in the developed world and it is now considered as a global
health burden ( Zimmet et al., 2001 ). Peripheral insulin resistance, deregu-
lated hepatic glucose production and inadequate insulin secretion charac-
terize T2DM. Furthermore, this disease involves defects in insulin signaling
due to reduced insulin receptor function and downstream phosphorylation
events ( Lee and White, 2004 ). Recent reports using genetically obese (ob/
ob) or high-fat diet (HFD)-induced obese mice identified an increase in
UPR markers in the liver and adipose tissues ( Ozcan et al., 2004 ). Moreover,
elevated ER stress markers, such as GRP78, XBP1s, phosphorylated eIF2a
and JNK, are detected in the liver and adipose tissue of obese insulin-resistant
individuals ( Boden et al., 2008 ). Additionally, JNK activation via UPR is asso-
ciated with insulin resistance via phosphorylation of IRS-1. Hotamisligil's
group described a causal link between ER stress and the development of
metabolic diseases like insulin resistance and T2DM. Using different cell cul-
ture and mouse models, they showed that obesity causes ER stress. Moreover,
mice deficient in the XBP-1 protein develop insulin resistance, demonstrating
that ER stress is a central feature of peripheral insulin resistance and T2DM at
the molecular and cellular level ( Ozcan et al., 2004 ). In another more recent
study, XBP-1 was shown to interact with the transcription factor FOXO1, a
key regulator of gluconeogenesis, and promote its proteasomal degradation.
Moreover, hepatic overexpression of XBP-1 results in significantly reduced
blood glucose levels and increased glucose tolerance in mouse models of
insulin resistance and type 1 and 2 diabetes. All these changes are accompa-
nied by a reduction in hepatic FoxO1, revealing that XBP-1 regulates glucose
homeostasis in response to ER stress ( Zhou et al., 2011 ).