Identification and Characterization of a Novel CREB‐H‐induced Hepatokine Implicating in Lipid Metabolism

Abstract

CREB‐H, a crucial transcription factor highly expressed in liver and small intestine, is critically involved in transactivation of lipid metabolism genes. CREB‐H is induced transcriptionally by fasting and has been implicated in triglyceride clearance. Hypertriglyceridemia observed in patients carrying loss‐of‐function CREB‐H mutations and in CREB‐H‐null mice is a proof of CREB‐H importance in lipid homeostasis. To decode the CREB‐H enigma in lipid homeostasis, we set off to discover and characterize new CREB‐H targets. Here, we identified a novel CREB‐H‐induced secretory protein, named Faci2, which might represent a novel hepatokine implicating in lipid metabolism and various metabolic disorders. Significant induction of Faci2 by active CREB‐HΔTC was observed in both animals and cultured cells. Additionally, endogenous hepatic expression of Faci2 in mice was highly induced by fasting in which CREB‐H is crucially required. Strikingly, forced hepatic expression of Faci2 by adeno‐associated virus in mice altered their lipid homeostasis. Animal weight gain and serum triglyceride level were significantly reduced whereas serum non‐esterified fatty acid level was elevated. Besides, Faci2 overexpression in cells or exogenous supplementation of purified Faci2 protein to cells boosted intracellular triglyceride level which is suggestive of extracellular signaling function of Faci2 in lipid homeostasis. Altogether, we have discovered a novel hepatokine induced by CREB‐H and shown that Faci2 plays an important role in lipid homeostasis. Our work sheds light on the biological significance of a novel CREB‐H‐induced hepatokine in lipid homeostasis. The new knowledge gained will instruct future development of therapeutics for various metabolic diseases such as non‐alcoholic fatty liver disease and dyslipidemias.