Autophagy in Disease - Protein Misfolding and Cellular Stress in Disease and Aging - page 84

pathways. However, in the case of pressure overload stress in
cardiomyocytes, enhanced levels of autophagy produce adverse
consequences. Many questions concerning the role of autophagy
in heart disease remain to be fully resolved, including the connec-
tions between autophagy and atherosclerosis ( 49 ).

It has been suggested that autophagy may play significant roles in
three areas of liver physiology: (1) the balance of nutrients and
energy resulting from neonatal adaptation, fasting, and metabolic
disturbance, (2) the removal of misfolded proteins resulting from
genetic mutations, pathological stimulation or ER stress, and
(3) turnover of organelles such as mitochondria, peroxisomes,
and ER under normal or pathophysiological conditions resulting
from a range of chemical treatments, hypoxia, ischemia, and
oxidative stress ( 12 ). The disturbance of autophagy function in
the liver could lead to metabolic imbalance, inflammation, cell
death, cirrhosis, and hepatocellular carcinoma ( 12 ) (Table 1 ).

3.4. Liver Disease

3.5. Infection,
Immunity, and Crohn's
Disease

Autophagy has emerged as a central component of antimicrobial
host defense against diverse bacterial (both gram-positive and gram-
negative), parasitic (protozoa and fungi), and viral (including
both RNA and DNA viruses) infections. In addition to pathogen
degradation (sometimes referred to as xenophagy), autophagy
has other functions during infection such as innate and adaptive
immune activation (antigen presentation, immune cell develop-
ment and homeostasis, and intestinal homeostasis) ( 50 ) and cell
survival (nutrient generation, degradation of damaged proteins,
and organelles and possibly degradation of pro-death and cytolytic
molecules). As autophagy is an important host defense pathway,
microbes, and viruses have also evolved mechanisms to evade,
subvert, or exploit autophagic pathways. However, some patho-
gens are able to modulate cellular components of autophagy in a
unique manner in order to establish an environmental niche and
promote pathogenesis ( 51-53 ) (Table 1 ).
Recently autophagy has attracted attention as a contributor
to Crohn's disease (CD), an inflammatory bowel disease affecting
the small intestine. On the basis of genetic linkage data, polymor-
phisms in two genes, one ( IRGM1 ) encoding an autophagy-
inducing signalling molecule and the other ( ATG16L1 ) a
component of the ubiquitin-like conjugation system involved in
AP membrane expansion, have been reported as being strongly
associated with the development of CD ( 54-57 ). The pathogenic
mechanisms of CD may involve a dysregulated immune response
to commensal bacteria, altered mucosal barrier function and/or
defects in bacterial clearance. It is plausible that defects in
autophagy could contribute to one or more of these potential
pathogenic mechanisms, however, the precise contribution of
autophagy to CD remains to be elucidated.