Abstract
The endoplasmic reticulum (ER)-resident basic leucine zipper (bZIP) transcription factor c-AMP responsive element binding protein H (CREBH/CREB3L3) is exclusively expressed in the liver and intestine. Physiologically, CREBH is intrinsically linked to nutritional homeostasis via its regulation on fatty acid β-oxidation, lipid droplet process, very low-density lipoprotein metabolism, gluconeogenesis, and iron metabolism. Pathologically, CREBH enhances hepatic acute-phase response gene expression (e.g., C-reactive protein and serum amyloid P-component) and mediates nutrient-surplus induced metabolic inflammation. Hyperactivation of CREBH in metabolic inflammation further contributes to the development of hyperlipidemia, lipotoxicity, non-alcoholic fatty liver disease, and potentially non-alcoholic steatohepatitis. This review highlights recent findings that delineate the interactions between CREBH and peroxisome proliferator activated receptor α (PPARα), fibroblast growth factor 21 (FGF21), fat-specific protein 27 (FSP27), and lipoprotein metabolism with a focus on the molecular and biochemical mechanisms that underlie the development of metabolic inflammation, non-alcoholic fatty liver disease and inflammatory associated bone disease.
Highlights
Introduction andCREB3L1-4) are highly conserved amongst metazoa with near identical DNA binding domains, suggesting they share over-1.1
The prior being a chronic lowgrade metabolic inflammation associated with pathologies of metabolic syndrome, including type-2 diabetes and obesity and mediated by protein kinases PKC, C-Jun N-terminal kinase and PKR as well as CREBH and suppressor of cytokine signalling proteins;[31,75,76] the latter being characterized by aberrant release of fatty acid (FA) causing white adipose tissue (WAT) to develop an immunogenic phenotype characterized by increased expression of inflammatory cytokines and chemokines, such as TNFα and monocyte chemoattractant protein-1 (MCP-1), decreased anti-inflammatory adiponectin and adipokines and recruitment of macrophages and T-cells
CREBH is a major regulator of numerous essential metabolic pathways, serving to modulate endoplasmic reticulum (ER)-stress, maintain homeostasis of lipid, glucose, iron and bone metabolism, and to facilitate the APR
Summary
Regulation of CREBH expression is complex, occurring via a combination of circadian rhythm,[5,23] prandial status,[24] ER stress as a result of nutritional imbalance,[19] and innate immune challenge (Figure 1). This is further complicated by tissue specificity of CREBH. Hepatocyte nuclear factor 4α (HNF4α) (in complex with PGC1α) is essential for hepatic expression of CREBH. Gastrointestinal expression of CREBH is independent of HNF4α; instead, the gastrointestinal enriched HNF4γ is suggested to act as an HNF4α substitute for intestinal CREBH expression.[16]
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