Abstract
Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat accumulates in the liver of patients without a prior history of alcohol abuse. The most severe form, nonalcoholic steatohepatitis (NASH), often leads to hepatic fibrosis and cirrhosis with ensuing complications. To date, there is no pharmacologic treatment for NASH. The biological effects of CCN3, specifically its role in the regulation of inflammation, reactive oxygen species production and angiogenesis, have been recently established. Additional data suggests that CCN3 is associated with the development of tumors in the liver yet may be protective of liver fibrogenesis. Currently, the role of CCN3 in NAFLD/NASH remains unexplored. Therefore, the objective of our investigation was to decipher the role of myeloid-deficient CCN3 in the pathogenesis of NASH and the underlying mechanisms of CCN3 in modulation of hepatic function. Wild type and myeloid CCN3-deficient mice were fed a methionine- and choline-deficient diet to induced NASH. Increased lipid, cholesterol, and cholesterol ester accumulation was observed in myeloid CCN3-deficient mice when compared to the control group. This disease state was associated with alterations of key genes involved in lipid synthesis, β-oxidation and lipid uptake. Additionally, the levels of important molecules critical for inflammation, ROS generation, ER stress and liver injury were significantly elevated; as was the observed severity of hepatic apoptosis and necroptosis. Therefore, CCN3 is critical for protection from hepatic apoptosis and necroptosis in our induced NASH model and our findings suggest that CCN3 can be exploited as a therapeutic target for the treatment of NASH.
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Abbreviations
- ACC:
-
acetyl-CoA carboxylase
- ALT:
-
alanine aminotransferase
- AST:
-
aspartate aminotransferase
- CCN:
-
Cyr61/CTGF/NOV
- CD36:
-
cluster of differentiation 36
- CHOP:
-
C/EBP homologous protein
- Cyr61:
-
cysteine-rich 61
- CTGF:
-
connective tissue growth factor
- DHE:
-
dihydroethidium
- ELOVL-6:
-
elongation of very long chain fatty acid protein-6
- ER:
-
endoplasmic reticulum
- FASN:
-
fatty acid synthase
- IL:
-
interleukin
- L-CPT-1:
-
carnitine palmitoyltransferase I (L-CPT-1)
- MCD:
-
methionine- choline- deficient
- NAFLD:
-
nonalcoholic fatty liver disease
- NASH:
-
nonalcoholic steatohepatitis
- NOV:
-
nephroblastoma overexpressed
- Nrf2:
-
nuclear factor (erythroid-derived 2)-like 2
- PCR:
-
polymerase chain reaction
- PPAR:
-
peroxisome proliferator-activated receptor
- PCG-1:
-
peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- qPCR:
-
quantitative polymerase chain reaction
- RIPK:
-
receptor-interacting serine/threonine-protein kinase
- ROS:
-
reactive oxygen species
- SCD-1:
-
stearoyl-Coenzyme A desaturase-1
- SREBP-1:
-
sterol regulatory element binding protein-1
- TNFα:
-
tumor necrosis factor alpha
- TUNEL:
-
terminal deoxynucleotidyl transferase nick end labeling
- dUTP:
-
deoxyuridine triphosphate
- XBP-1:
-
X-box binding protein 1
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Acknowledgements
This work was supported by NIH grants AA021390 and HL117759 (ZL) and National Natural Science Foundation of China grants NSFC-81400290 (XH) and NSFC-81070342 (QZ).
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Wu, W., Hu, X., Zhou, X. et al. Myeloid deficiency of CCN3 exacerbates liver injury in a mouse model of nonalcoholic fatty liver disease. J. Cell Commun. Signal. 12, 389–399 (2018). https://doi.org/10.1007/s12079-017-0432-4
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DOI: https://doi.org/10.1007/s12079-017-0432-4