**3.2 ER stress and metabolic disorders**

In the field of metabolism, ER stress causes metabolic disorders in various tissues and, in the liver, ER stress is considered to be involved in the development of insulin resistance and fatty liver disease [16]. It was first reported that ER stress markers were enhanced in the liver of mouse models of obesity and diabetes [17, 18]. Systemic Xbp1 knockout mice are a well-known model of impaired ER stress response, which shows elevated ER stress, impaired insulin signaling, and glucose intolerance [17]. Moreover, administration of chemical chaperones improves not only insulin resistance and hyperglycemia but also fatty liver [19]. Similarly, suppressed activation of the PERK branch of the ER stress response cascade, by dephosphorylation of eIF2 alpha, also improves hepatosteatosis as well as glucose tolerance [20]. Thus generally, impaired responses to chronic ER stress or excessive chronic ER stress in the liver are considered to result in hepatic insulin resistance and fatty liver disease, although these phenotypes were not necessarily replicated in other models [21, 22], and XBP-1 s protein was also reported to upregulate lipogenic genes [23].

However, some years later, ER stress response was reported to be suppressed, contrary to the earlier reports, and a controversy was thus raised about whether ER stress and ER stress response are enhanced or suppressed in obesity and diabetes. Activity of nATF6 is suppressed in the liver of mouse models of obesity and diabetes [24]. Moreover, binding with p85, one of the key downstream molecules of insulin signaling, is required for XBP-1 s protein to be translocated to the nucleus and exert its activity as a transcription factor in the liver. In model mice of obesity and diabetes, however, insulin-mediated nuclear translocation of XBP-1 s protein is impaired due to insulin resistance [25, 26]. A similar insulin signaling-mediated nuclear translocation of XBP-1 s protein was recently reported in other tissues as well [27]. Interestingly, XBP-1 s protein regulates gluconeogenesis rather directly, via ubiquitination and consequent proteasome-mediated degradation of FoxO1, a transcription factor involved in the induction of gluconeogenic enzymes in the liver [28] (**Figure 3**).

Taken together, insulin signaling appears not only to promote protein synthesis, but also to be involved in quality control of synthesized proteins. Moreover, XBP-1 s is a multi-talented molecule which is closely associated with regulation of not only ER stress response but also glucose and lipid metabolism.

*ER Stress Response Failure and Steatohepatitis Comorbid with Diabetes DOI: http://dx.doi.org/10.5772/intechopen.100054*

#### **Figure 3.**

*XBP-1s protein in the regulation of glucose metabolism: insulin-mediated nuclear translocation and regulation of gluconeogenesis.*

#### **3.3 ER stress in the liver and diseases in humans**

In humans, some ER stress markers are known to be affected by insulin resistance and nonalcoholic steatohepatitis (NASH). NASH is associated with phosphorylation of JNK and lower XBP-1 s protein levels [29]. Expression of sXBP1 and BiP mRNA is not correlated with insulin resistance [30], but is lowered by gastric bypass surgery [31]. We and colleagues previously reported that IRS-1 expression in the liver is negatively correlated with fibrosis [32], suggesting the protective role of insulin signaling against the development of NASH. These reports, however, did not distinguish ER stress and ER stress response or NASH in diabetic patients and NASH in non-diabetic patients.
