A novel CREBH-derived hepatokine regulates triglyceride metabolism

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Project Summary: Hypertriglyceridemia, a condition in which blood triglyceride (TG) levels are elevated, is a major risk factor of metabolic and cardiovascular diseases, such as type-2 diabetes, atherosclerosis, and non- alcoholic fatty liver disease. Clearance of plasma TG is primarily mediated by lipoprotein lipase (LPL). LPL, expressed by the parenchymal cells of lipolytic tissues, is transported to capillary lumen by the endothelial cell transporter GPIHBP1, where it hydrolyzes plasma TG for local uptake into peripheral tissues. Although significant progress has been made, the fine-tune regulation of LPL activity as well as TG lipolysis and partitioning into peripheral tissues remain to be further elucidated. In the last funding cycle, we revealed that the endoplasmic reticulum (ER)-tethered, liver-enriched transcriptional factor CREBH functions as a diurnal metabolic regulator that integrates circadian regulation to energy homeostasis. Recently, we discovered that the C-terminal fragment of CREBH (CREBH-C), produced through Regulated Intramembrane Proteolysis (RIP), is secreted from the liver into circulation as a “hepatokine” upon energy demands. Secreted CREBH-C interacts with angiopoietin-like 3 (ANGPTL3) and ANGPTL8 to prevent the inhibitory interactions between ANGPTL3/8 and LPL, thus promoting LPL activity and TG partitioning into peripheral tissues. Circulatory CREBH-C promotes TG clearance and partitioning and mitigates hypertriglyceridemia caused by over-nutrition. These lines of evidence prompted us to hypothesize that ER membrane-tethered CREBH is processed by RIP to produce a novel hepatokine, CREBH-C, which interacts with ANGPTLs to regulate intravascular LPL activity, TG partitioning into peripheral tissues, and whole-body metabolism. CREBH-C intervention may increase metabolic flexibility and thus mitigate hypertriglyceridemia and the associated metabolic disorders. In this application, we will utilize molecular and cellular approaches, genetic animal models, as well as innovative LPL-monitoring and lipid-tracing approaches to define a novel hepatokine, CREBH-C, and its regulatory roles in LPL activity and TG homeostasis: Aim 1, to define the mechanistic pathway by which the ER membrane-tethered CREBH is processed to produce a secreted form of CREBH; Aim 2, to delineate the regulation and mechanistic basis by which CREBH-C interacts with ANGPTL3/8 to regulate LPL activity; Aim 3, to determine the functional significance of CREBH-C in regulating TG partitioning and whole- body metabolism and in mitigating hypertriglyceridemia and the associated metabolic phenotypes. Within the funding period, we anticipate defining a new paradigm that a stress-induced protein fragment, derived from the ER membrane protein CREBH, can function as a potent hepatokine to regulate lipid homeostasis and whole-body metabolism. Revealing this unprecedented regulatory pathway for CREBH and its derived hepatokine will have important implications in therapeutic interventions toward the control of hypertriglyceridemia and the associated metabolic and cardiovascular disorders.