CREBH: A Complex Array of Regulatory Mechanisms in Nutritional Signaling, Metabolic Inflammation, and Metabolic Disease

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.

REDD1 deletion and treadmill running increase liver hepcidin and gluconeogenic enzymes in male mice

“…The greater liver Ppargc1a expression with REDD1 deletion in the present study may be driving the genotypic difference in liver Hamp , whereby PGC1α provides increased stabilisation of CREB3L3 protein on the hepcidin promoter in REDD1 KO mice despite no difference in Creb3l3 expression between genotypes. Greater PGC1α and CREB3L3 activity is supported by greater hepatic gene expression of Pck1 and Pygl with REDD1 deletion and greater Pck1 expression with exercise, indicating transcriptional promotion of hepatic gluconeogenesis and glycogenolysis by PGC1α and CREB3L3 ( 30 ) . These data further support the role of gluconeogenesis in the hepcidin response and reduced dietary iron absorption following a bout of prolonged exercise ( 8 , 11 , 15 ) and indicate the glucoregulatory role of REDD1 and its possible impact on iron metabolism.…”

Inducible hepatic expression of CREBH mitigates diet-induced obesity, insulin resistance, and hepatic steatosis in mice

“…Activation of CREBH occurs in response to a multiplicity of stimuli (5), and this liver-enriched transcription factor in turn upregulates genes that restore lipid and glucose homeostasis (11,27). Among these is Fgf21, which is secreted from the liver and promotes weight loss and improves glucose tolerance and hepatic steatosis (14-16, 18, 19).…”

“…CREBH is transcriptionally controlled by peroxisome proliferator activated receptor α and the glucocorticoid receptor (4). It is activated in liver by fasting, circadian signals, uptake of plasma fatty acids, inflammation, and ER stress to control a multiplicity of genes, including those that regulate apolipoprotein biosynthesis, fatty acid metabolism, lipid droplet formation, and the innate immune response (5). CREBH is induced in mouse liver under conditions of overnutrition, including obesity, insulin resistance (IR), and experimental nonalcoholic fatty liver disease (NAFLD), playing complex regulatory roles in lipid homeostasis (6)(7)(8), hepatic gluconeogenesis (9), clearance of plasma triglycerides (8), and lipid droplet accumulation within hepatocytes (10,11).…”

Metabolism and Inflammation: New Synergies and Insights

“…In addition, Su's team describes how nutrient‐surplus induced hyperactivation of CREBH (c‐AMP responsive element binding protein H), greatly affects hepatic glucose metabolism and lipotoxicity with a concomitant acute‐phase response. [ 4 ]…”