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

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.

Immunoregulatory Roles of Osteopontin in Diseases

“…In NASH, OPN regulates macrophages and promotes liver injury through activation of various signaling pathways [ 24 , 34 , 50 ]. It promotes macrophage M1 polarization by activating the JAK1/STAT1/HMGB1 signaling pathway in hepatocytes, resulting in the increased expression of proinflammatory cytokines and liver injury [ 24 ].…”

“…When silencing sOPN expression in hepatocytes or inhibiting sOPN release in NASH, macrophage infiltration, inflammation and fibrosis in the liver were reduced [ 34 ]. Moreover, intrahepatic OPN signaling by CREBZFOPN stimulates the activation of HSCs and fibrogenic cells and induces liver fibrosis and inflammation, worsening NASH severity [ 50 ]. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) is upregulated via YAP/TAZ-TEAD in NASH livers and consequently promotes liver fibrosis by activating the NOTCH pathway and enhancing OPN production [ 51 ].…”

Androgen synthesis cell‐specific CREBZF deficiency alters adrenal cortex steroid secretion and develops behavioral abnormalities in adult male mice

“…However, due to conformational changes caused by a lack of an Asn residue in N‐terminus, CREBZF has to exert transcriptional regulation by heterodimerization 23,26,27 . Based on the above characteristics, several additional studies have shown that CREBZF is widely involved in physiological processes such as metabolism, 28–32 cancers, 33–37 apoptosis, 38–40 autophagy, 41 and unfolded protein response (UPR) 42–45 . In recent years, we 40,46,47 and others 48–50 have validated the expression pattern of CREBZF in the gonads, indicating that CREBZF plays important roles in gametogenesis, embryo implantation, and steroid hormonal regulation.…”

“…However, due to conformational changes caused by a lack of an Asn residue in N-terminus, CREBZF has to exert transcriptional regulation by heterodimerization. 23,26,27 Based on the above characteristics, several additional studies have shown that CREBZF is widely involved in physiological processes such as metabolism, [28][29][30][31][32] cancers, [33][34][35][36][37] apoptosis, [38][39][40] autophagy, 41 and unfolded protein response (UPR). [42][43][44][45] In recent years, we 40,46,47 and others [48][49][50] have validated the…”

Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes

“…[ 8 ] CREBZF increases hepatic stellate cell activation and fibrosis by stimulating osteopontin in NASH. [ 9 ] Moreover, CREBZF inhibits liver regeneration by repressing STAT3. [ 10 ] Although transcriptional networks of CREBZF in liver metabolism and bZIP proteins are involved in inflammation, such as the C/EBP family, whether CREBZF regulates inflammatory pathways and insulin resistance remains unknown.…”