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 46

METABOLIC SYNDROME
Glucose intolerance
Hyperlipidemia
Hypertension
Obesity

HYPERHOMO-
CYSTEINEMIA

LEPTIN
RESISTANCE

Neuron
ER stress
Muscle Liver Adipocyte

ER stress (endothelial cell)

NAFLD/AFLD INSULIN RESISTANCE ATHEROSCLEROSIS

Steatosis LDL/cholesterol deposition

ER stress
( β cell)

ER stress
(hepatocyte)

Inflammation

TYPE 2 DIABETES
( β cell failure)

Risk factor

Foam cells

Steatohepatitis

ER stress (macrophage)

ER stress
(hepatocyte,
liver NKT cell)

Advanced Lesion
(Foam cell apoptosis)

Thrombosis

Liver failure
Hepatocellular carcinoma

ER stress (neuron,
cardiac myocytes)

Ischemia (brain, heart)

Fig. 4. Roles of ER stress in progression of the metabolic syndrome and of hyperhomocysteinemia to diseases. ER stress
plays a central role in the onset of non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), type 2
diabetes, and atherosclerosis in hyperhomocysteinemia. Legend: Black arrows - Progression of the metabolic syndrome
to disease, gray arrows - progression of hyperhomocysteinemia to disease.

(POMC), which is processed to the anorexic (appetite-decreasing)
a-melanocyte-stimulating hormone (aMSH) in LRb/POMC
neurons. At the same time, leptin, by acting through LRb,
inhibits synthesis of the orexigenic (appetite-stimulating) peptide
hormones neuropeptide Y (NPY) and agouti-related peptide
(AgRP) by NPY/AgRP neurons. At the molecular level, the unli-
ganded, dimeric LRb is associated with the protein tyrosine kinase
JAK2. Conformational changes in the LRb upon leptin binding
trigger trans -autophosphorylation and tyrosine phosphorylation
of LRb by JAK2. As a consequence SRC homology 2 (SH2)
domain containing proteins such as the transcription factor STAT3
and the tyrosine phosphatase, SHP-2 bind to tyrosine phospho-
rylated LRb. Tyrosine phosphorylation of STAT3 triggers nuclear
translocation and subsequent transcriptional activation of STAT3
target genes. Tyrosine phosphorylation of insulin receptor (IR)
substrate (IRS) proteins activates phosphoinositide (PI) 3-kinase
(PI3K) signaling (cf. below) promoting growth, cell division, and