Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis.

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.

• Authors: Laura J Dixon, Michael Berk, Samjhana Thapaliya, Bettina G Papouchado, Ariel E Feldstein
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 92 Issue 5 Pg. 713-23 (May 2012) ISSN: 1530-0307 [Electronic] United States
• PMID: 22411067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Actins
• Antigens, Differentiation
• Collagen Type I
• Csrp2 protein, mouse
• Interleukin-1beta
• LIM Domain Proteins
• Muscle Proteins
• Nuclear Proteins
• Transforming Growth Factor beta
• Tumor Necrosis Factor-alpha
• alpha-smooth muscle actin, mouse
• monocyte-macrophage differentiation antigen
• Clodronic Acid
• Methionine
• Casp3 protein, mouse
• Caspase 3
• Caspase 1

Topics

• Actins (metabolism)
• Animals
• Antigens, Differentiation (metabolism)
• Caspase 1 (deficiency, genetics, metabolism)
• Caspase 3 (blood, metabolism)
• Choline Deficiency (complications, metabolism, pathology)
• Clodronic Acid (pharmacology)
• Collagen Type I (metabolism)
• Fatty Liver (chemically induced, metabolism, pathology)
• Hepatic Stellate Cells (metabolism, pathology)
• Hepatocytes (metabolism, pathology)
• Inflammation (metabolism)
• Interleukin-1beta (metabolism)
• Kupffer Cells (drug effects, metabolism)
• LIM Domain Proteins (metabolism)
• Liver (metabolism, pathology)
• Liver Cirrhosis (chemically induced, metabolism, pathology)
• Methionine (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle Proteins (metabolism)
• Nuclear Proteins (metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)