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Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis
- Source :
- Laboratory investigation; a journal of technical methods and pathology
- Publication Year :
- 2012
-
Abstract
- Non-alcoholic steatohepatitis (NASH) is typically associated with pro-apoptotic caspase activation. A potential role for pro-inflammatory caspases remains incompletely understood. Our aims were to examine a potential role of caspase-1 in the development of liver damage and fibrosis in NASH. C57BL/6 wild type (WT) developed marked steatohepatitis, activation, fibrosis and increased hepatic caspase-1 and interleukin-1β expression when placed on the methionine- and choline-deficient (MCD) diet. Marked caspase-1 activation was detected in the liver of MCD-fed mice. Hepatocyte and non-parenchymal fractionation of the livers further demonstrated that caspase-1 activation after MCD feeding was mainly localized to non-parenchymal cells. Caspase-1-knockout (Casp1(-/-)) mice on the MCD diet showed marked reduction in mRNA expression of genes involved in inflammation and fibrogenesis (tumor necrosis factor-α was 7.6-fold greater in WT vs Casp1(-/-) MCD-fed mice; F4/80 was 1.5-fold greater in WT vs Casp1(-/-) MCD-fed mice; α-smooth muscle actin was 3.2-fold greater in WT vs Casp1(-/-) MCD-fed mice; collagen 1-α was 7.6-fold greater in WT vs Casp1(-/-) MCD-fed mice; transforming growth factor-β was 2.4-fold greater in WT vs Casp1(-/-) MCD-fed mice; cysteine- and glycine-rich protein 2 was 3.2-fold greater in WT vs Casp1(-/-) MCD-fed mice). Furthermore, Sirius red staining for hepatic collagen deposition was significantly reduced in Casp1(-/-) MCD-fed mice compared with WT MCD-fed animals. However, serum alanine aminotransferase levels, caspase-3 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells were similar in Casp1(-/-) and WT mice on the MCD diet. Selective Kupffer cell depletion by clodronate injection markedly suppressed MCD-induced caspase-1 activation and protected mice from fibrogenesis and fibrosis associated with this diet. The conclusion of this study is that it uncovers a novel role for caspase-1 in inflammation and fibrosis during NASH development.
- Subjects :
- Liver Cirrhosis
Pathology
Interleukin-1beta
Muscle Proteins
chemistry.chemical_compound
Mice
0302 clinical medicine
Methionine
Fibrosis
Transforming Growth Factor beta
nonalcoholic steatohepatitis (NASH)
Caspase
Mice, Knockout
0303 health sciences
biology
Caspase 3
Kupffer cell
Fatty liver
Caspase 1
Nuclear Proteins
LIM Domain Proteins
3. Good health
Choline Deficiency
medicine.anatomical_structure
Liver
caspases
030211 gastroenterology & hepatology
medicine.medical_specialty
Kupffer Cells
Collagen Type I
Article
Pathology and Forensic Medicine
03 medical and health sciences
inflammasome
Internal medicine
medicine
Hepatic Stellate Cells
Animals
Molecular Biology
Sirius Red
030304 developmental biology
Inflammation
Tumor Necrosis Factor-alpha
fibrosis
nutritional and metabolic diseases
Cell Biology
medicine.disease
Antigens, Differentiation
eye diseases
Actins
Fatty Liver
Mice, Inbred C57BL
Endocrinology
chemistry
Terminal deoxynucleotidyl transferase
Hepatic stellate cell
biology.protein
Hepatocytes
Steatohepatitis
Clodronic Acid
Nonalcoholic fatty liver disease (NAFLD)
Subjects
Details
- ISSN :
- 15300307
- Volume :
- 92
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Laboratory investigation; a journal of technical methods and pathology
- Accession number :
- edsair.doi.dedup.....102093d92b12390d88cb7d33941e5f47