Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression

Hepatology. 2023 Nov 1;78(5):1492-1505. doi: 10.1097/HEP.0000000000000042. Epub 2023 Jan 3.

Abstract

Background and aims: NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity.

Approach and results: Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus -mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH.

Conclusions: Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Disease Models, Animal
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fibrosis
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Osteopontin* / genetics
  • Osteopontin* / metabolism

Substances

  • Basic-Leucine Zipper Transcription Factors
  • CREBZF protein, human
  • Osteopontin