title: 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.affiliation: Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western University, Cleveland, OH, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Dixon
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Samjhana
authors.initials: S
authors.lastname: Thapaliya
authors.forename: Bettina G
authors.initials: BG
authors.lastname: Papouchado
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000097:blood / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D000943:Antigens, Differentiation; D024042:Collagen Type I; C484376:Csrp2 protein, mouse; D053583:Interleukin-1beta; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse; C036763:monocyte-macrophage differentiation antigen; D004002:Clodronic Acid; D008715:Methionine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020170:Caspase 1