Consequences of Stress in the Secretary Pathway: The ER Stress Response and Its Role in the Metabolic Syndrome - Protein Misfolding and Cellular Stress in Disease and Aging - page 48

ER stress also elevates ROS levels in cells ( 65, 66 ), which inhibit
JNK phosphatases by oxidizing catalytic cysteines ( 67 ), leading to
the accumulation of phosphorylated, activated JNK. TRB3,
whose expression is induced by CHOP ( 68, 69 ), binds to and
inhibits AKT ( 70 ). XBP-1 positively controls expression of several
lipogenic genes such as diacylglycerol- O -acyltransferase ( DGAT2 ),
acetyl CoA carboxylase b ( ACC2 ), and stearoyl-CoA desaturase 1
( SCD1 ) and is required for hepatic triglyceride secretion ( 71 ). In
enterocytes, IRE1b mediates degradation of the mRNA for
microsomal triglyceride transfer protein (MTP) ( 72 ), which is
required for assembly of chylomicrons in the ER. ire1b −/− mice
display hyperlipidemia ( 72 ), suggesting that IRE1b contributes
to lipid homeostasis and plays a positive role in prevention of the
metabolic syndrome. However, IRE1b mRNA levels are decreased
by a cholesterol-rich or high-fat diet ( 72 ). Thus, stimulation of
lipid synthesis by an activated UPR may lead to self-perpetuating
ER stress and UPR activation and chronic, ever-worsening insulin
resistance.

3.3. Type 2 Diabetes

Type 2 diabetes is characterized by a ~60% loss in b cells in islets,
accumulation of islet amyloid, and increased b cell apoptosis ( 73 ).
ER stress contributes to b cell failure and apoptosis in type 2 dia-
betes (Fig. 4 ). b cells respond to insulin resistance by increasing
their insulin secretion. As insulin resistance becomes more severe
and ever more insulin is required to stimulate IR receptor signal-
ing, b cells cross a threshold of insulin synthesis that triggers ER
stress, ultimately leading to b cell apoptosis. Deletion of CHOP
protects b cells from apoptosis, but also exacerbates diet or genet-
ically induced obesity ( 74, 75 ). Mouse models with mutations in
the proinsulin gene preventing proper folding of proinsulin are
associated with ER stress, apoptotic loss of b cells, and develop-
ment of diabetes ( 76-81 ). A second major secretory client pro-
tein of b cells is islet amyloid precursor protein (IAPP).
Accumulation of IAPP oligomers in b cells contributes to b cell
failure ( 82, 83 ). Human, but not rodent, IAPP forms nonselec-
tive ion channels and disrupts membrane function ( 83, 84 ). ER
stress, through depletion of chaperones, may contribute to aggre-
gation of IAPP in b cells. IAPP oligomers may act in similar ways
as neurodegenerative amyloids, that is, amyloid b, to cause ER
stress ( 85 ) and b cell death.

The early stage of NAFLD is hepatosteatosis. Elevated plasma
free fatty acid and homocysteine levels cause ER stress, leading
to insulin resistance. Insulin resistance increases lipid secretion
by adipocytes, exacerbating ER stress (Fig. 1 ). Hepatosteatosis is
associated with markers of ER stress such as XBP-1 splicing and
BiP induction ( 63 ), suggesting that a decrease in the fluidity of
the ER membrane interferes with function of critical ER membrane

3.4. Non-alcoholic
Fatty Liver Disease