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

Lab Invest. 2012 May;92(5):713-23. doi: 10.1038/labinvest.2012.45. Epub 2012 Mar 12.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Antigens, Differentiation / metabolism
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Caspase 3 / blood
  • Caspase 3 / metabolism
  • Choline Deficiency / complications
  • Choline Deficiency / metabolism
  • Choline Deficiency / pathology
  • Clodronic Acid / pharmacology
  • Collagen Type I / metabolism*
  • Fatty Liver / chemically induced
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Hepatic Stellate Cells / metabolism*
  • Hepatic Stellate Cells / pathology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Inflammation / metabolism*
  • Interleukin-1beta / metabolism
  • Kupffer Cells / drug effects
  • Kupffer Cells / metabolism*
  • LIM Domain Proteins / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / 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


  • 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