Abstract
Non-alcoholic steatohepatitis (NASH) is a disorder marked by alterations in hepatic lipid homeostasis as well as liver injury in the form of cell death, inflammation and fibrosis. Research into the pathophysiology of NASH is dynamic. New concepts from the fields of cell biology, microbiology, immunology and genetics are being tested for their applicability to NASH; discoveries in each of these areas are enriching our understanding of this complex disease. This review summarizes how recent developments from the bench and bedside are merging with more traditional concepts to reshape our view of NASH pathogenesis. Highlights include human studies that emphasize the role of de novo lipogenesis in NASH and experimental work uncovering a role for the inflammasome in NASH. Genetic predispositions to NASH are being clarified, and intestinal microbiome is emerging as a determinant of fatty liver. These unique ideas are now taking their place within an integrated picture of NASH pathogenesis.
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Abbreviations
- ApoB:
-
apolipoprotein B
- ATF6:
-
activating transcription factor 6
- CB2:
-
cannabinoid receptor 2
- CCL2:
-
C-C chemokine ligand 2
- c-Src:
-
proto-oncogene tyrosine-protein kinase
- CYP2E1:
-
cytochrome P450 2E1
- DNL:
-
de novo lipogenesis
- ER:
-
endoplasmic reticulum
- GCKR:
-
glucokinase regulator
- HSC:
-
hepatic stellate cells
- IL-1β:
-
interleukin-1β
- IRE1:
-
inositol-requiring protein 1
- JNK:
-
Jun N-terminal kinase
- LPAAT:
-
lysophosphatidic acid acyltransferase
- LPC:
-
lysophosphatidylcholine
- LYPAL1:
-
lysophospholipase-like 1
- MRC:
-
mitochondrial respiratory chain
- NAFL:
-
non-alcoholic fatty liver
- NASH:
-
non-alcoholic steatohepatitis
- NCAN:
-
neurocan
- NLRP:
-
NOD-like receptor proteins
- NOD:
-
nucleotide-binding oligomerization domain
- PERK:
-
RNA-dependent protein kinase-like ER kinase
- PNPLA3:
-
patatin-like phospholipase domain-containing 3
- PPARδ:
-
peroxisome proliferator-activated receptor-δ
- PPP1R3B:
-
protein phosphatase 1 regulatory subunit 3B
- RANTES:
-
regulated on activation normal T cell expressed and secreted (CCL5)
- ROS:
-
reactive oxygen species
- SFA:
-
saturated fatty acid
- SREBP-1:
-
sterol regulatory element binding protein-1
- TCA:
-
tricarboxylic acid cycle
- TLR:
-
Toll-like receptor
- UPR:
-
unfolded protein response
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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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Acknowledgments
The authors are supported by the following grants: T32 DK060414 (CCD), R01 DK068450 (JJM), P30 DK026743 (JJM).
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Caroline C. Duwaerts declares no conflicts of interest.
Jacquelyn J. Maher declares no conflicts of interest.
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Duwaerts, C.C., Maher, J.J. Mechanisms of Liver Injury in Non-Alcoholic Steatohepatitis. Curr Hepatology Rep 13, 119–129 (2014). https://doi.org/10.1007/s11901-014-0224-8
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DOI: https://doi.org/10.1007/s11901-014-0224-8